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Chen, Chin Ho

Positions:

Professor of Surgery

Surgery, Surgical Sciences
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1991

Ph.D. — University of North Carolina at Chapel Hill

Grants:

Quinolizidines as Novel HIV-1 Entry Inhibitors

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 17, 2016
End Date
July 31, 2017

Plant Anti-HIV Agents

Administered By
Surgery, Surgical Sciences
AwardedBy
University of North Carolina - Chapel Hill
Role
Principal Investigator
Start Date
July 01, 2009
End Date
June 30, 2017

Intervening with Latent HIV-1 Infection using Gnidimacrin

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 2014
End Date
March 31, 2017

Regulation of PD-1 as a strategy against chronic HIV-1 infection

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
May 20, 2013
End Date
April 30, 2016

Betulinic acid derivatives as anti-HIV agents

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
February 01, 2006
End Date
April 30, 2016

Small Molecules that Regulate Proteasome Activity

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
January 01, 2009
End Date
November 30, 2013

Identification of anti-HIV agent(s) from Sophora Alkaloids

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
April 01, 2008
End Date
March 31, 2011

Dynamic Envelope interactions and HIV-1 Neutralization

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 2003
End Date
December 31, 2008

TM-SU Interaction in the Native HIV/SIV Env

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 2001
End Date
May 31, 2008

The Molecular Target of the HIV-1 Entry Inhibitor IC9564

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 2003
End Date
April 30, 2006

Mechanisms Of Cd8+ Noncytolytic Inhibition Of Hiv-1

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
July 01, 1996
End Date
June 30, 1999

Neutralization Determinants Of A Primary Hiv-1 Isolate

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
March 01, 1997
End Date
February 28, 1999

Peptide Models Of Two Helical Regions In Gp41 Ectodomain

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 30, 1990
End Date
February 28, 1999

Duke University Center For Aids Research

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
July 01, 1993
End Date
June 30, 1994
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Publications:

Anti-HIV natural products (28): preparation of conjugate for 3-O-acyl betulin derivative and AZT as anti-HIV agents.

Authors
Wada, S; Tanaka, N; Chen, CH; Morris-Natschke, SL; Lee, KH; Kashiwada, Y
MLA Citation
Wada, S, Tanaka, N, Chen, CH, Morris-Natschke, SL, Lee, KH, and Kashiwada, Y. "Anti-HIV natural products (28): preparation of conjugate for 3-O-acyl betulin derivative and AZT as anti-HIV agents." Planta medica 81.S 01 (December 14, 2016): S1-S381.
PMID
27975981
Source
epmc
Published In
Planta Medica
Volume
81
Issue
S 01
Publish Date
2016
Start Page
S1
End Page
S381

Incorporation of Privileged Structures into Bevirimat Can Improve Activity against Wild-Type and Bevirimat-Resistant HIV-1.

Two "privileged fragments", caffeic acid and piperazine, were integrated into bevirimat producing new derivatives with improved activity against HIV-1/NL4-3 and NL4-3/V370A carrying the most prevalent bevirimat-resistant polymorphism. The activity of one of these, 18c, was increased by 3-fold against NL4-3 and 51-fold against NL4-3/V370A. Moreover, 18c is a maturation inhibitor with improved metabolic stability. Our study suggested that integration of privileged motifs into promising natural product skeletons is an effective strategy for discovering potent derivatives.

Authors
Zhao, Y; Gu, Q; Morris-Natschke, SL; Chen, C-H; Lee, K-H
MLA Citation
Zhao, Y, Gu, Q, Morris-Natschke, SL, Chen, C-H, and Lee, K-H. "Incorporation of Privileged Structures into Bevirimat Can Improve Activity against Wild-Type and Bevirimat-Resistant HIV-1." Journal of medicinal chemistry 59.19 (October 2016): 9262-9268.
PMID
27676157
Source
epmc
Published In
Journal of Medicinal Chemistry
Volume
59
Issue
19
Publish Date
2016
Start Page
9262
End Page
9268
DOI
10.1021/acs.jmedchem.6b00461

Two new ursane-type triterpenoid saponins from Elsholtzia bodinieri.

Two new ursane-type triterpenoid saponins, bodiniosides M (1) and N (2), along with three known saponins, oblonganosides I (3), pseudobuxussaponin B (4) and bodinioside A (5), were isolated from the aerial parts of Elsholtzia bodinieri. The structures of compounds 1 and 2 were characterized by spectroscopic data as well as acid hydrolysis and GC analysis as 3-O-β-D-xylopyranosyl-19α-hydroxy-23-acetoxy-urs-12(13)-en-28-oic acid 28-O-α-L-rhamnopyranosyl-(1-2)-β-D-glucopyranoside and 3-O-β-D-glucopyranosyl-2α,19α-dihydroxy-urs-12(13)-en-28,20β-lactone. Compounds 1 and 5 exhibited potent anti-HCV activities in vitro with a selective index of 6.53 and 4.41, respectively.

Authors
Zhong, J-D; Zhao, X-W; Chen, X-Q; Li, H-M; Chen, C-H; Xia, X-S; Li, R-T
MLA Citation
Zhong, J-D, Zhao, X-W, Chen, X-Q, Li, H-M, Chen, C-H, Xia, X-S, and Li, R-T. "Two new ursane-type triterpenoid saponins from Elsholtzia bodinieri." Archives of pharmacal research 39.6 (June 2016): 771-777.
PMID
27138284
Source
epmc
Published In
Archives of Pharmacal Research
Volume
39
Issue
6
Publish Date
2016
Start Page
771
End Page
777
DOI
10.1007/s12272-016-0750-8

Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitor Agents: Optimization of Diarylanilines with High Potency against Wild-Type and Rilpivirine-Resistant E138K Mutant Virus.

Three series (6, 13, and 14) of new diarylaniline (DAAN) analogues were designed, synthesized, and evaluated for anti-HIV potency, especially against the E138K viral strain with a major mutation conferring resistance to the new-generation non-nucleoside reverse transcriptase inhibitor drug rilpivirine (1b). Promising new compounds were then assessed for physicochemical and associated pharmaceutical properties, including aqueous solubility, log P value, and metabolic stability, as well as predicted lipophilic parameters of ligand efficiency, ligand lipophilic efficiency, and ligand efficiency-dependent lipophilicity indices, which are associated with ADME property profiles. Compounds 6a, 14c, and 14d showed high potency against the 1b-resistant E138K mutated viral strain as well as good balance between anti-HIV-1 activity and desirable druglike properties. From the perspective of optimizing future NNRTI compounds as clinical trial candidates, computational modeling results provided valuable information about how the R(1) group might provide greater efficacy against the E138K mutant.

Authors
Liu, N; Wei, L; Huang, L; Yu, F; Zheng, W; Qin, B; Zhu, D-Q; Morris-Natschke, SL; Jiang, S; Chen, C-H; Lee, K-H; Xie, L
MLA Citation
Liu, N, Wei, L, Huang, L, Yu, F, Zheng, W, Qin, B, Zhu, D-Q, Morris-Natschke, SL, Jiang, S, Chen, C-H, Lee, K-H, and Xie, L. "Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitor Agents: Optimization of Diarylanilines with High Potency against Wild-Type and Rilpivirine-Resistant E138K Mutant Virus." Journal of medicinal chemistry 59.8 (April 12, 2016): 3689-3704.
PMID
27070547
Source
epmc
Published In
Journal of Medicinal Chemistry
Volume
59
Issue
8
Publish Date
2016
Start Page
3689
End Page
3704
DOI
10.1021/acs.jmedchem.5b01827

Carolignans from the Aerial Parts of Euphorbia sikkimensis and Their Anti-HIV Activity.

Seven new carolignans, including two pairs of enantiomers (±)-erythro-7'-methylcarolignan E (1a/1b) and (±)-threo-7'-methylcarolignan E (2a/2b), (+)-threo-carolignan E (3a), (+)-erythro-carolignan E (4a), and (-)-erythro-carolignan Z (5), together with four known lignans (3b, 4b, 6, and 7) and six polyphenols (8-13) were isolated from the aerial parts of Euphorbia sikkimensis. The structures of the new compounds were elucidated by spectroscopic analysis, and their absolute configurations were determined by electronic circular dichroism calculations. Seven of the isolates were examined for anti-HIV effects, and compounds 1a and 1b showed moderate anti-HIV activity with EC50 values of 6.3 and 5.3 μM.

Authors
Jiang, C; Luo, P; Zhao, Y; Hong, J; Morris-Natschke, SL; Xu, J; Chen, C-H; Lee, K-H; Gu, Q
MLA Citation
Jiang, C, Luo, P, Zhao, Y, Hong, J, Morris-Natschke, SL, Xu, J, Chen, C-H, Lee, K-H, and Gu, Q. "Carolignans from the Aerial Parts of Euphorbia sikkimensis and Their Anti-HIV Activity." Journal of natural products 79.3 (March 2016): 578-583.
PMID
26756779
Source
epmc
Published In
Journal of Natural Products
Volume
79
Issue
3
Publish Date
2016
Start Page
578
End Page
583
DOI
10.1021/acs.jnatprod.5b01012

Aloperine and Its Derivatives as a New Class of HIV-1 Entry Inhibitors.

A quinolizidine-type alkaloid aloperine was found to inhibit HIV-1 infection by blocking HIV-1 entry. Aloperine inhibited HIV-1 envelope-mediated cell-cell fusion at low micromolar concentrations. To further improve the antiviral potency, more than 30 aloperine derivatives with a variety of N12-substitutions were synthesized. Among them, 12d with an N-(1-butyl)-4-trifluoromethoxy-benzamide side chain showed the most potent anti-HIV-1 activity with EC50 at 0.69 μM. Aloperine derivatives inhibited both X4 and R5 HIV-1 Env-mediated cell-cell fusions. In addition, both BMS-806, a compound representing a class of HIV-1 gp120-targeting small molecules in clinical trials, and resistant and sensitive HIV-1 Env-mediated cell-cell fusions were equally sensitive to aloperine derivatives. These results suggest that aloperine and its derivatives are a new class of anti-HIV-1 entry inhibitors.

Authors
Dang, Z; Zhu, L; Lai, W; Bogerd, H; Lee, K-H; Huang, L; Chen, C-H
MLA Citation
Dang, Z, Zhu, L, Lai, W, Bogerd, H, Lee, K-H, Huang, L, and Chen, C-H. "Aloperine and Its Derivatives as a New Class of HIV-1 Entry Inhibitors." ACS medicinal chemistry letters 7.3 (March 2016): 240-244.
PMID
26985308
Source
epmc
Published In
ACS Medicinal Chemistry Letters
Volume
7
Issue
3
Publish Date
2016
Start Page
240
End Page
244
DOI
10.1021/acsmedchemlett.5b00339

Fluorinated betulinic acid derivatives and evaluation of their anti-HIV activity.

Several fluorinated derivatives of the anti-HIV maturation agent bevirimat (1) were synthesized and evaluated for anti-HIV replication activity. The modified positions were the C-2, C-3, C-28, and C-30 positions, either directly on the betulinic acid (2) skeleton or in the attached side chains. Compound 18, which has a trifluoromethyl group added to C-30 of its isopropenyl group, exhibited similar potency to 1 against HIV-1NL4-3. In total, our current studies support our prior conclusion that C-30 allylic modification is unlikely to be a pharmacophore for anti-HIV activity, but could be a meaningful route to manipulate other properties of 2-related compounds.

Authors
Li, J; Goto, M; Yang, X; Morris-Natschke, SL; Huang, L; Chen, C-H; Lee, K-H
MLA Citation
Li, J, Goto, M, Yang, X, Morris-Natschke, SL, Huang, L, Chen, C-H, and Lee, K-H. "Fluorinated betulinic acid derivatives and evaluation of their anti-HIV activity." Bioorganic & medicinal chemistry letters 26.1 (January 2016): 68-71.
PMID
26598461
Source
epmc
Published In
Bioorganic & Medicinal Chemistry Letters
Volume
26
Issue
1
Publish Date
2016
Start Page
68
End Page
71
DOI
10.1016/j.bmcl.2015.11.029

Two Small Molecules Block Oral Epithelial Cell Invasion by Porphyromons gingivalis.

Porphyromonas gingivalis is a keystone pathogen of periodontitis. One of its bacterial characteristics is the ability to invade various host cells, including nonphagocytic epithelial cells and fibroblasts, which is known to facilitate P. gingivalis adaptation and survival in the gingival environment. In this study, we investigated two small compounds, Alop1 and dynasore, for their role in inhibition of P. gingivalis invasion. Using confocal microscopy, we showed that these two compounds significantly reduced invasion of P. gingivalis and its outer membrane vesicles into human oral keratinocytes in a dose-dependent manner. The inhibitory effects of dynasore, a dynamin inhibitor, on the bacterial entry is consistent with the notion that P. gingivalis invasion is mediated by a clathrin-mediated endocytic machinery. We also observed that microtubule arrangement, but not actin, was altered in the host cells treated with Alop1 or dynasore, suggesting an involvement of microtubule in this inhibitory activity. This work provides an opportunity to develop compounds against P. gingivalis infection.

Authors
Ho, M-H; Huang, L; Goodwin, JS; Dong, X; Chen, C-H; Xie, H
MLA Citation
Ho, M-H, Huang, L, Goodwin, JS, Dong, X, Chen, C-H, and Xie, H. "Two Small Molecules Block Oral Epithelial Cell Invasion by Porphyromons gingivalis." PloS one 11.2 (January 2016): e0149618-.
PMID
26894834
Source
epmc
Published In
PloS one
Volume
11
Issue
2
Publish Date
2016
Start Page
e0149618
DOI
10.1371/journal.pone.0149618

Stelleralides D-J and Anti-HIV Daphnane Diterpenes from Stellera chamaejasme.

Bioassay-guided fractionation of a petroleum ether extract of the roots of Stellera chamaejasme led to the isolation of seven new (stelleralides D-J, 1-7) and 12 known (8-19) daphnane diterpenoids. The structures and relative configurations of 1-7 were established on the basis of extensive spectroscopic analysis, including HRESIMS and comprehensive NMR techniques. All isolates were evaluated for anti-HIV activity in MT4 cells. All compounds tested, except 2, showed anti-HIV activity, and, especially, five 1α-alkyldaphnane diterpenoids (3, 4, 5, 10, and 11) exhibited extremely potent anti-HIV activity, with EC50 values of 0.06-1.1 nM and selectivity index values of more than 10,000.

Authors
Yan, M; Lu, Y; Chen, C-H; Zhao, Y; Lee, K-H; Chen, D-F
MLA Citation
Yan, M, Lu, Y, Chen, C-H, Zhao, Y, Lee, K-H, and Chen, D-F. "Stelleralides D-J and Anti-HIV Daphnane Diterpenes from Stellera chamaejasme." Journal of natural products 78.11 (November 12, 2015): 2712-2718.
PMID
26562066
Source
epmc
Published In
Journal of Natural Products
Volume
78
Issue
11
Publish Date
2015
Start Page
2712
End Page
2718
DOI
10.1021/acs.jnatprod.5b00660

Gnidimacrin, a Potent Anti-HIV Diterpene, Can Eliminate Latent HIV-1 Ex Vivo by Activation of Protein Kinase C β.

HIV-1-latency-reversing agents, such as histone deacetylase inhibitors (HDACIs), were ineffective in reducing latent HIV-1 reservoirs ex vivo using CD4 cells from patients as a model. This deficiency poses a challenge to current pharmacological approaches for HIV-1 eradication. The results of this study indicated that gnidimacrin (GM) was able to markedly reduce the latent HIV-1 DNA level and the frequency of latently infected cells in an ex vivo model using patients peripheral blood mononuclear cells. GM induced approximately 10-fold more HIV-1 production than the HDACI SAHA or romidepsin, which may be responsible for the effectiveness of GM in reducing latent HIV-1 levels. GM achieved these effects at low picomolar concentrations by selective activation of protein kinase C βI and βII. Notably, GM was able to reduce the frequency of HIV-1 latently infected cells at concentrations without global T cell activation or stimulating inflammatory cytokine production. GM merits further development as a clinical trial candidate for latent HIV-1 eradication.

Authors
Lai, W; Huang, L; Zhu, L; Ferrari, G; Chan, C; Li, W; Lee, K-H; Chen, C-H
MLA Citation
Lai, W, Huang, L, Zhu, L, Ferrari, G, Chan, C, Li, W, Lee, K-H, and Chen, C-H. "Gnidimacrin, a Potent Anti-HIV Diterpene, Can Eliminate Latent HIV-1 Ex Vivo by Activation of Protein Kinase C β." Journal of medicinal chemistry 58.21 (November 2015): 8638-8646.
PMID
26509731
Source
epmc
Published In
Journal of Medicinal Chemistry
Volume
58
Issue
21
Publish Date
2015
Start Page
8638
End Page
8646
DOI
10.1021/acs.jmedchem.5b01233

Flavonoids Isolated from Heat-Processed Epimedium koreanum and Their Anti-HIV-1 Activities

Authors
Li, H-M; Zhou, C; Chen, C-H; Li, R-T; Lee, K-H
MLA Citation
Li, H-M, Zhou, C, Chen, C-H, Li, R-T, and Lee, K-H. "Flavonoids Isolated from Heat-Processed Epimedium koreanum and Their Anti-HIV-1 Activities." Helvetica Chimica Acta 98.8 (August 2015): 1177-1187.
Source
crossref
Published In
Helvetica Chimica Acta
Volume
98
Issue
8
Publish Date
2015
Start Page
1177
End Page
1187
DOI
10.1002/hlca.201500123

Discovery of novel non-covalent inhibitors selective to the β5-subunit of the human 20S proteasome.

A series of linear peptides (6a-6o) were designed based on the known non-covalent 20S proteasome inhibitors TMC-95A and compound 5 via a fragment-based approach. These compounds were synthesized and evaluated against the chymotrypsin-like activity of the human 20S proteasome. Three of them (6d, 6e and 6k) were potent inhibitors with IC50 values at the submicromolar level. These three compounds were selective to the β5-subunit and showed no obvious inhibition against trypsin-like and caspase-like activities of the human 20S proteasome. Docking study of the most potent compound 6e revealed its key interactions with the β5-subunit of the 20S proteasome. These findings have provided a new chemical template for non-covalent proteasome inhibitors, which is ready for further structural optimization to improve both potency and subunit selectivity.

Authors
Xu, K; Wang, K; Yang, Y; Yan, D-A; Huang, L; Chen, C-H; Xiao, Z
MLA Citation
Xu, K, Wang, K, Yang, Y, Yan, D-A, Huang, L, Chen, C-H, and Xiao, Z. "Discovery of novel non-covalent inhibitors selective to the β5-subunit of the human 20S proteasome." European journal of medicinal chemistry 98 (June 2015): 61-68.
PMID
26005024
Source
epmc
Published In
European Journal of Medicinal Chemistry
Volume
98
Publish Date
2015
Start Page
61
End Page
68
DOI
10.1016/j.ejmech.2015.05.023

Phenolic diterpenoid derivatives as anti-influenza a virus agents.

A series of diterpenoid derivatives based on podocarpic acid were synthesized and evaluated as anti-influenza A virus agents. Several of the novel podocarpic acid derivatives exhibited nanomolar activities against an H1N1 influenza A virus (A/Puerto Rico/8/34) that was resistant to two anti-influenza drugs, oseltamivir and amantadine. This class of compounds inhibits the influenza virus by targeting the viral hemagglutinin-mediated membrane fusion. These results indicated that podocarpic acid derivatives may serve as potential drug candidates to fight drug-resistant influenza A virus infections.

Authors
Dang, Z; Jung, K; Zhu, L; Xie, H; Lee, K-H; Chen, C-H; Huang, L
MLA Citation
Dang, Z, Jung, K, Zhu, L, Xie, H, Lee, K-H, Chen, C-H, and Huang, L. "Phenolic diterpenoid derivatives as anti-influenza a virus agents." ACS medicinal chemistry letters 6.3 (March 2015): 355-358.
PMID
25815159
Source
epmc
Published In
ACS Medicinal Chemistry Letters
Volume
6
Issue
3
Publish Date
2015
Start Page
355
End Page
358
DOI
10.1021/ml500533x

Discovery of novel 5-fluoro-N(2),N(4)-diphenylpyrimidine-2,4-diamines as potent inhibitors against CDK2 and CDK9.

Based on a 3D-QSAR pharmacophore derived from a diverse set of known cyclin-dependent kinase 9 (CDK9) inhibitors and a composite pharmacophore extracted from the complex structure of flavopiridol (FVP)-CDK9, thirty novel 5-fluoro-N(2),N(4)-diphenylpyrimidine-2,4-diamine derivatives were designed and synthesized. Initial tests against four tumor cell lines with the sulforhodamine B (SRB) assay identified a series of potent compounds with GI50 values at lower micromolar or submicromolar level. Most of the highly cytotoxic compounds exhibited potent inhibitory activities against both CDK2/cyclin E1 and CDK9/cyclin T1. Notably, inhibitions against the two enzymes were generally correlated well with the cytotoxicity of these compounds. Appreciable inhibition was also observed for selected compounds in the anti-HIV-1 assay. Docking studies on compounds 6d and 9g provided conducive clues to further structural optimization.

Authors
Gao, J; Fang, C; Xiao, Z; Huang, L; Chen, C-H; Wang, L-T; Lee, K-H
MLA Citation
Gao, J, Fang, C, Xiao, Z, Huang, L, Chen, C-H, Wang, L-T, and Lee, K-H. "Discovery of novel 5-fluoro-N(2),N(4)-diphenylpyrimidine-2,4-diamines as potent inhibitors against CDK2 and CDK9." MedChemComm 6.3 (March 2015): 444-454.
PMID
25914804
Source
epmc
Published In
MedChemComm
Volume
6
Issue
3
Publish Date
2015
Start Page
444
End Page
454
DOI
10.1039/c4md00412d

Fimbriae-mediated outer membrane vesicle production and invasion of Porphyromonas gingivalis.

Porphyromonas gingivalis is a keystone periopathogen that plays an essential role in the progress of periodontitis. Like other gram-negative bacteria, the ability of P. gingivalis to produce outer membrane vesicles is a strategy used to interact with, and survive within its biological niches. Here we compared the protein components associated with vesicles derived from a fimbriated strain (33277) and an afimbriated strain (W83) of P. gingivalis using proteomic analyses. Some well-known virulence factors were identified in vesicles from both strains, such as gingipains and hemagglutinin. In contrast, FimC, FimD, and FimE, minor components of long fimbriae were found exclusively in 33277 vesicles, while proteins with a tetratricopeptide repeat (TPR) domain were unique to W83 vesicles. We found that significantly more 33277 than W83 vesicles were internalized into human oral keratinocytes and gingival fibroblasts. Interestingly, FimA, a well-known adhesin responsible for the attachment and invasion of P. gingivalis into host cells, was not essential for the invasive capabilities of P. gingivalis vesicles. Rather minor components of long fimbriae were required for an efficient invasive activity of vesicles. The most striking finding was that P. gingivalis strains lacking or having a reduced FimA expression showed a significant reduction in vesiculation. These results suggest that production and pathogenicity of P. gingivalis vesicles may largely depend on expression of the fim locus, and that the integration of vesicle production and pathogenicity with fimbrial expression may allow P. gingivalis to confer upon itself certain functional advantages.

Authors
Mantri, CK; Chen, C-H; Dong, X; Goodwin, JS; Pratap, S; Paromov, V; Xie, H
MLA Citation
Mantri, CK, Chen, C-H, Dong, X, Goodwin, JS, Pratap, S, Paromov, V, and Xie, H. "Fimbriae-mediated outer membrane vesicle production and invasion of Porphyromonas gingivalis." MicrobiologyOpen 4.1 (February 2015): 53-65.
PMID
25524808
Source
epmc
Published In
MicrobiologyOpen
Volume
4
Issue
1
Publish Date
2015
Start Page
53
End Page
65
DOI
10.1002/mbo3.221

Functional Advantages of Porphyromonas gingivalis Vesicles.

Porphyromonas gingivalis is a keystone pathogen of periodontitis. Outer membrane vesicles (OMVs) have been considered as both offense and defense components of this bacterium. Previous studies indicated that like their originating cells, P. gingivalis vesicles, are able to invade oral epithelial cells and gingival fibroblasts, in order to promote aggregation of some specific oral bacteria and to induce host immune responses. In the present study, we investigated the invasive efficiency of P. gingivalis OMVs and compared results with that of the originating cells. Results revealed that 70-90% of human primary oral epithelial cells, gingival fibroblasts, and human umbilical vein endothelial cells carried vesicles from P. gingivalis 33277 after being exposed to the vesicles for 1 h, while 20-50% of the host cells had internalized P. gingivalis cells. We also detected vesicle-associated DNA and RNA and a vesicle-mediated horizontal gene transfer in P. gingivalis strains, which represents a novel mechanism for gene transfer between P. gingivalis strains. Moreover, purified vesicles of P. gingivalis appear to have a negative impact on biofilm formation and the maintenance of Streptococcus gordonii. Our results suggest that vesicles are likely the best offence weapon of P. gingivalis for bacterial survival in the oral cavity and for induction of periodontitis.

Authors
Ho, M-H; Chen, C-H; Goodwin, JS; Wang, B-Y; Xie, H
MLA Citation
Ho, M-H, Chen, C-H, Goodwin, JS, Wang, B-Y, and Xie, H. "Functional Advantages of Porphyromonas gingivalis Vesicles." PloS one 10.4 (January 2015): e0123448-.
PMID
25897780
Source
epmc
Published In
PloS one
Volume
10
Issue
4
Publish Date
2015
Start Page
e0123448
DOI
10.1371/journal.pone.0123448

Porphyromonas gingivalis-mediated Epithelial Cell Entry of HIV-1.

HIV-1 relies on the host's cell machinery to establish a successful infection. Surface receptors, such as CD4, CCR5, and CXCR4 of T cells and macrophages, are essential for membrane fusion of HIV-1, an initiate step in viral entry. However, it is not well defined how HIV-1 infects CD4-negative mucosal epithelial cells. Here we show that there is a specific interaction between HIV-1 and an invasive oral bacterium, Porphyromonas gingivalis. We found that HIV-1 was trapped on the bacterial surface, which led to internalization of HIV-1 virions as the bacteria invaded CD4-negative epithelial cells. Both bacterial and viral DNA was detected in HeLa and TERT-2 cells exposed to the HIV-1-P. gingivalis complexes 2 hr after the initial infection but not in cells exposed to HIV-1 alone. Moreover, epithelial cell entry of HIV-1 was positively correlated with invasive activity of the P. gingivalis strains tested, even when the binding affinities of HIV-1 to these strains were similar. Finally, it was demonstrated that the viral DNA was integrated into the genome of the host epithelial cells. These results reveal a receptor-independent HIV-1 entry into epithelial cells, which may be relevant in HIV transmission in other mucosal epithelia where complex microbial communities can be found.

Authors
Mantri, CK; Chen, C; Dong, X; Goodwin, JS; Xie, H
MLA Citation
Mantri, CK, Chen, C, Dong, X, Goodwin, JS, and Xie, H. "Porphyromonas gingivalis-mediated Epithelial Cell Entry of HIV-1." Journal of dental research 93.8 (August 2014): 794-800.
PMID
24874702
Source
epmc
Published In
Journal of Dental Research
Volume
93
Issue
8
Publish Date
2014
Start Page
794
End Page
800
DOI
10.1177/0022034514537647

Identification and synthesis of quinolizidines with anti-influenza a virus activity.

Influenza A virus infection causes a contagious respiratory illness that poses a threat to human health. However, there are limited anti-influenza A therapeutics available, which is further compounded by the emergence of drug resistant viruses. In this study, Sophora quinolizidine alkaloids were identified as a new class of anti-influenza A virus agents. Among the tested Sophora alkaloids, dihydroaloperine exhibited the most potent activity with an EC50 of 11.2 μM. The potency of the quinolizidine alkaloids was improved by approximately 5-fold with chemical modifications on the aloperine molecule. These compounds were effective against an H1N1 influenza A virus that was resistant to the two antiflu drugs oseltamivir and amantadine. The identification of the quinolizidine alkaloids as effective and novel anti-influenza A agents may aid in the development of new therapeutics.

Authors
Dang, Z; Jung, K; Zhu, L; Lai, W; Xie, H; Lee, K-H; Huang, L; Chen, C-H
MLA Citation
Dang, Z, Jung, K, Zhu, L, Lai, W, Xie, H, Lee, K-H, Huang, L, and Chen, C-H. "Identification and synthesis of quinolizidines with anti-influenza a virus activity." ACS medicinal chemistry letters 5.8 (August 2014): 942-946.
PMID
25147619
Source
epmc
Published In
ACS Medicinal Chemistry Letters
Volume
5
Issue
8
Publish Date
2014
Start Page
942
End Page
946
DOI
10.1021/ml500236n

Optimization of the antiviral potency and lipophilicity of halogenated 2,6-diarylpyridinamines as a novel class of HIV-1 NNRTIS.

Nineteen new halogenated diarylpyridinamine (DAPA) analogues modified at the phenoxy C-ring were synthesized and evaluated for anti-HIV activity and certain drug-like properties. Ten compounds showed high anti-HIV activity (EC50 <10 nM). In particular, (E)-6-(2''-bromo-4''-cyanovinyl-6''-methoxy)phenoxy-N(2) -(4'-cyanophenyl)pyridin-2,3-diamine (8 c) displayed low-nanomolar antiviral potency (3-7 nM) against wild-type and drug-resistant viral strains bearing the E138K or K101E mutations, which are associated with resistance to rilvipirine (1 b). Compound 8 c exhibited much lower resistance fold changes (RFC: 1.1-2.1) than 1 b (RFC: 11.8-13.0). Compound 8 c also exhibited better metabolic stability (in vitro half-life) than 1 b in human liver microsomes, possessed low lipophilicity (clog D: 3.29; measured log P: 3.31), and had desirable lipophilic efficiency indices (LE>0.3, LLE>5, LELP<10). With balanced potency and drug-like properties, 8 c merits further development as an anti-HIV drug candidate.

Authors
Wu, Z-Y; Liu, N; Qin, B; Huang, L; Yu, F; Qian, K; Morris-Natschke, SL; Jiang, S; Chen, CH; Lee, K-H; Xie, L
MLA Citation
Wu, Z-Y, Liu, N, Qin, B, Huang, L, Yu, F, Qian, K, Morris-Natschke, SL, Jiang, S, Chen, CH, Lee, K-H, and Xie, L. "Optimization of the antiviral potency and lipophilicity of halogenated 2,6-diarylpyridinamines as a novel class of HIV-1 NNRTIS." ChemMedChem 9.7 (July 2014): 1546-1555.
PMID
24895029
Source
epmc
Published In
Chemmedchem
Volume
9
Issue
7
Publish Date
2014
Start Page
1546
End Page
1555
DOI
10.1002/cmdc.201400075

Optimization of the antiviral potency and lipophilicity of halogenated 2,6-diarylpyridinamines as a novel class of HIV-1 NNRTIS

Nineteen new halogenated diarylpyridinamine (DAPA) analogues modified at the phenoxy C-ring were synthesized and evaluated for anti-HIV activity and certain drug-like properties. Ten compounds showed high anti-HIV activity (EC50<10 nM). In particular, (E)-6-(2′′-bromo- 4′′-cyanovinyl-6′′-methoxy)phenoxy-N2- (4′-cyanophenyl)pyridin-2,3-diamine (8 c) displayed low-nanomolar antiviral potency (3-7 nM) against wild-type and drug-resistant viral strains bearing the E138K or K101E mutations, which are associated with resistance to rilvipirine (1 b). Compound 8 c exhibited much lower resistance fold changes (RFC: 1.1-2.1) than 1 b (RFC: 11.8-13.0). Compound 8 c also exhibited better metabolic stability (in vitro half-life) than 1 b in human liver microsomes, possessed low lipophilicity (clog D: 3.29; measured log P: 3.31), and had desirable lipophilic efficiency indices (LE>0.3, LLE>5, LELP<10). With balanced potency and drug-like properties, 8 c merits further development as an anti-HIV drug candidate. Taking the lead! Among 19 new halogenated diarylpyridinamine (DAPA) analogues, (E)-6-(2′′-bromo- 4′′-cyanovinyl-6′′-methoxy)phenoxy-N2- (4′-cyanophenyl)pyridin-2,3-diamine (8 c) displays low-nanomolar antiviral potency (3-7 nM) against wild-type HIV and E138K or K101E mutant strains; it also exhibits promising drug-like properties. Compound 8 c merits development as an anti-HIV drug candidate. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Authors
Wu, ZY; Liu, N; Qin, B; Huang, L; Yu, F; Qian, K; Morris-Natschke, SL; Jiang, S; Chen, CH; Lee, KH; Xie, L
MLA Citation
Wu, ZY, Liu, N, Qin, B, Huang, L, Yu, F, Qian, K, Morris-Natschke, SL, Jiang, S, Chen, CH, Lee, KH, and Xie, L. "Optimization of the antiviral potency and lipophilicity of halogenated 2,6-diarylpyridinamines as a novel class of HIV-1 NNRTIS." ChemMedChem 9.7 (January 1, 2014): 1546-1555.
Source
scopus
Published In
Chemmedchem
Volume
9
Issue
7
Publish Date
2014
Start Page
1546
End Page
1555
DOI
10.1002/cmdc.201400075

Two new cadinane-type sesquiterpenes from the Chinese liverwort Frullania serrata.

Two new cadinane-type sesquiterpenes, frullanic acid (1) and frullanic acid methyl ester (2), together with four known bibenzyls, brittonin B (3), 3,3'-dimethoxy-4,5-methylenedioxybibenzyl (4), 3,4,5,3',4'-penlamethoxybibenzyl (5) and (±)-3-(4'-methoxybenzyl)-5,6-dimethoxyphtbalide (6), were isolated from the Chinese liverwort Frullania serrata. The structures of the new metabolites were elucidated by analysing the spectroscopic data (1D NMR, 2D NMR, HR-ESI-MS and IR). The absolute configurations of compounds 1 and 2 were determined by comparing the experimental and calculated electronic circular dichroism spectra predicted by using time-dependent density functional theory as well as the CD exciton chirality method.

Authors
Li, R-J; Zhu, R-X; Zhao, Y; Morris-Natschke, SL; Chen, C-H; Wang, S; Zhang, J-Z; Zhou, J-C; Lou, H-X; Lee, K-H
MLA Citation
Li, R-J, Zhu, R-X, Zhao, Y, Morris-Natschke, SL, Chen, C-H, Wang, S, Zhang, J-Z, Zhou, J-C, Lou, H-X, and Lee, K-H. "Two new cadinane-type sesquiterpenes from the Chinese liverwort Frullania serrata." Natural product research 28.19 (January 2014): 1519-1524.
PMID
24969508
Source
epmc
Published In
Natural Product Research
Volume
28
Issue
19
Publish Date
2014
Start Page
1519
End Page
1524
DOI
10.1080/14786419.2014.909416

In-depth analysis of the interaction of HIV-1 with cellular microRNA biogenesis and effector mechanisms.

UNLABELLED: The question of how HIV-1 interfaces with cellular microRNA (miRNA) biogenesis and effector mechanisms has been highly controversial. Here, we first used deep sequencing of small RNAs present in two different infected cell lines (TZM-bl and C8166) and two types of primary human cells (CD4(+) peripheral blood mononuclear cells [PBMCs] and macrophages) to unequivocally demonstrate that HIV-1 does not encode any viral miRNAs. Perhaps surprisingly, we also observed that infection of T cells by HIV-1 has only a modest effect on the expression of cellular miRNAs at early times after infection. Comprehensive analysis of miRNA binding to the HIV-1 genome using the photoactivatable ribonucleoside-induced cross-linking and immunoprecipitation (PAR-CLIP) technique revealed several binding sites for cellular miRNAs, a subset of which were shown to be capable of mediating miRNA-mediated repression of gene expression. However, the main finding from this analysis is that HIV-1 transcripts are largely refractory to miRNA binding, most probably due to extensive viral RNA secondary structure. Together, these data demonstrate that HIV-1 neither encodes viral miRNAs nor strongly influences cellular miRNA expression, at least early after infection, and imply that HIV-1 transcripts have evolved to avoid inhibition by preexisting cellular miRNAs by adopting extensive RNA secondary structures that occlude most potential miRNA binding sites. IMPORTANCE: MicroRNAs (miRNAs) are a ubiquitous class of small regulatory RNAs that serve as posttranscriptional regulators of gene expression. Previous work has suggested that HIV-1 might subvert the function of the cellular miRNA machinery by expressing viral miRNAs or by dramatically altering the level of cellular miRNA expression. Using very sensitive approaches, we now demonstrate that neither of these ideas is in fact correct. Moreover, HIV-1 transcripts appear to largely avoid regulation by cellular miRNAs by adopting an extensive RNA secondary structure that occludes the ability of cellular miRNAs to interact with viral mRNAs. Together, these data suggest that HIV-1, rather than seeking to control miRNA function in infected cells, has instead evolved a mechanism to become largely invisible to cellular miRNA effector mechanisms.

Authors
Whisnant, AW; Bogerd, HP; Flores, O; Ho, P; Powers, JG; Sharova, N; Stevenson, M; Chen, C-H; Cullen, BR
MLA Citation
Whisnant, AW, Bogerd, HP, Flores, O, Ho, P, Powers, JG, Sharova, N, Stevenson, M, Chen, C-H, and Cullen, BR. "In-depth analysis of the interaction of HIV-1 with cellular microRNA biogenesis and effector mechanisms. (Published online)" MBio 4.2 (April 16, 2013): e000193-.
PMID
23592263
Source
pubmed
Published In
mBio
Volume
4
Issue
2
Publish Date
2013
Start Page
e000193
DOI
10.1128/mBio.00193-13

New betulinic acid derivatives for bevirimat-resistant human immunodeficiency virus type-1.

Bevirimat (1, BVM) is an anti-HIV agent that blocks HIV-1 replication by interfering with HIV-1 Gag-SP1 processing at a late stage of viral maturation. However, clinical trials of 1 have revealed a high baseline drug resistance that is attributed to naturally occurring polymorphisms in HIV-1 Gag. To overcome the drug resistance, 28 new derivatives of 1 were synthesized and tested against compound 1-resistant (BVM-R) HIV-1 variants. Among them, compound 6 exhibited much improved activity against several HIV-1 strains carrying BVM-R polymorphisms. Compound 6 was at least 20-fold more potent than 1 against the replication of NL4-3/V370A, which carries the most prevalent clinical BVM-R polymorphism in HIV-1 Gag-SP1. Thus, compound 6 merits further development as a potential anti-AIDS clinical trial candidate.

Authors
Dang, Z; Ho, P; Zhu, L; Qian, K; Lee, K-H; Huang, L; Chen, C-H
MLA Citation
Dang, Z, Ho, P, Zhu, L, Qian, K, Lee, K-H, Huang, L, and Chen, C-H. "New betulinic acid derivatives for bevirimat-resistant human immunodeficiency virus type-1." J Med Chem 56.5 (March 14, 2013): 2029-2037.
PMID
23379607
Source
pubmed
Published In
Journal of Medicinal Chemistry
Volume
56
Issue
5
Publish Date
2013
Start Page
2029
End Page
2037
DOI
10.1021/jm3016969

Isolation, structure determination, and anti-HIV evaluation of tigliane-type diterpenes and Biflavonoid from stellera chamaejasme

Five novel tigliane-type diterpenes, stelleracins A-E (3-7), a novel flavanone dimer, chamaeflavone A (8), and six known compounds were isolated from the roots of Stellera chamaejasme. Their structures were elucidated by extensive spectroscopic analyses. The isolated compounds were evaluated for anti-HIV activity in MT4 cells. New compounds 3-5 showed potent anti-HIV activity (EC90 0.00056-0.0068 μM) and relatively low or no cytotoxicity (IC50 4.4-17.2 μM). These new compounds represent promising new leads for development into anti-AIDS clinical trial candidates. © 2013 The American Chemical Society and American Society of Pharmacognosy.

Authors
Asada, Y; Sukemori, A; Watanabe, T; Malla, KJ; Yoshikawa, T; Li, W; Kuang, X; Koike, K; Chen, C-H; Akiyama, T; Qian, K; Nakagawa-Goto, K; Morris-Natschke, SL; Lu, Y; Lee, K-H
MLA Citation
Asada, Y, Sukemori, A, Watanabe, T, Malla, KJ, Yoshikawa, T, Li, W, Kuang, X, Koike, K, Chen, C-H, Akiyama, T, Qian, K, Nakagawa-Goto, K, Morris-Natschke, SL, Lu, Y, and Lee, K-H. "Isolation, structure determination, and anti-HIV evaluation of tigliane-type diterpenes and Biflavonoid from stellera chamaejasme." Journal of Natural Products 76.5 (2013): 852-857.
PMID
23611151
Source
scival
Published In
Journal of Natural Products
Volume
76
Issue
5
Publish Date
2013
Start Page
852
End Page
857
DOI
10.1021/np300815t

Synthesis of betulinic acid derivatives as entry inhibitors against HIV-1 and bevirimat-resistant HIV-1 variants.

Betulinic acid derivatives modified at the C28 position are HIV-1entry inhibitors such as compound A43D; however, modified at the C3 position instead of C28 give HIV-1 maturation inhibitor such as bevirimat. Bevirimat exhibited promising pharmacokinetic profiles in clinical trials, but its effectiveness was compromised by the high baseline drug resistance of HIV-1 variants with polymorphism in the putative drug binding site. In an effort to determine whether the viruses with bevirimat resistant polymorphism also altered their sensitivities to the betulinic acid derivatives that inhibit HIV-1 entry, a series of new betulinic acid entry inhibitors were synthesized and tested for their activities against HIV-1 NL4-3 and NL4-3 variants resistant to bevirimat. The results show that the bevirimat resistant viruses were approximately 5- to10-fold more sensitive to three new glutamine ester derivatives (13, 15 and 38) and A43D in an HIV-1 multi-cycle replication assay. In contrast, the wild type NL4-3 and the bevirimat resistant variants were equally sensitive to the HIV-1 RT inhibitor AZT. In addition, these three new compounds markedly improved microsomal stability compared to A43D.

Authors
Dang, Z; Qian, K; Ho, P; Zhu, L; Lee, K-H; Huang, L; Chen, C-H
MLA Citation
Dang, Z, Qian, K, Ho, P, Zhu, L, Lee, K-H, Huang, L, and Chen, C-H. "Synthesis of betulinic acid derivatives as entry inhibitors against HIV-1 and bevirimat-resistant HIV-1 variants." Bioorg Med Chem Lett 22.16 (August 15, 2012): 5190-5194.
PMID
22818973
Source
pubmed
Published In
Bioorganic & Medicinal Chemistry Letters
Volume
22
Issue
16
Publish Date
2012
Start Page
5190
End Page
5194
DOI
10.1016/j.bmcl.2012.06.080

Synthesis and biological evaluation of novel spin labeled 18β-glycyrrhetinic acid derivatives

Eighteen novel spin-labeled 18β-glycyrrhetinic acid (GA) derivatives were designed, synthesized, and evaluated for cytotoxicity against four human tumor cell lines (A-549, DU-145, KB and KBvin). Most of the derivatives showed more significant cytotoxicity than that of the parent compound GA. The best compound, 6j, with a tryptophan amino moiety and piperidine nitroxyl radical showed GI50 values of 13.7-15.0 μM, and was fivefold more potent than GA. In a mechanism of action study, compound 7a was confirmed as a 20S proteasome inhibitor in both in vitro and cell-based assays. These findings support further optimization efforts based on 18β-GA as a lead compound to develop potential anticancer drug candidates. © 2012 Elsevier Ltd. All rights reserved.

Authors
Liu, Y; Qian, K; Wang, C-Y; Chen, C-H; Yang, X; Lee, K-H
MLA Citation
Liu, Y, Qian, K, Wang, C-Y, Chen, C-H, Yang, X, and Lee, K-H. "Synthesis and biological evaluation of novel spin labeled 18β-glycyrrhetinic acid derivatives." Bioorganic and Medicinal Chemistry Letters 22.24 (2012): 7530-7533.
PMID
23122524
Source
scival
Published In
Bioorganic & Medicinal Chemistry Letters
Volume
22
Issue
24
Publish Date
2012
Start Page
7530
End Page
7533
DOI
10.1016/j.bmcl.2012.10.041

Synthesis of Lithocholic Acid Derivatives as Proteasome Regulators.

Accumulation of aberrant protein aggregates, such as amyloid beta peptide (Aβ), due to decreased proteasome activities might contribute to the neurodegeneration in Alzheimer's disease. In this study, lithocholic acid derivatives 3α-O-pimeloyl-lithocholic acid methyl ester (2) and its isosteric isomer (6) were found to activate the chymotrypsin-like activity of the proteasome at an EC(50) of 7.8 and 4.3 μM, respectively. Replacing the C24 methyl ester in 2 with methylamide resulted in a complete devoid of proteasome activating activity. Epimerizing the C3 substituent from an alpha to beta orientation transformed the activator into a proteasome inhibitor. Unlike the cellular proteasome activator PA28, proteasome activated by 2 was not inhibited by Aβ. Furthermore, 2 potently antagonized the inhibitory effect of Aβ on the proteasome. In summary, compound 2 represents a novel class of small molecules that not only activates the proteasome but also antagonizes the inhibitory effect of Aβ on the proteasome.

Authors
Dang, Z; Jung, K; Qian, K; Lee, K-H; Huang, L; Chen, C-H
MLA Citation
Dang, Z, Jung, K, Qian, K, Lee, K-H, Huang, L, and Chen, C-H. "Synthesis of Lithocholic Acid Derivatives as Proteasome Regulators." ACS Med Chem Lett 3.11 (2012): 925-930.
PMID
23330053
Source
pubmed
Published In
ACS Med Chem Lett
Volume
3
Issue
11
Publish Date
2012
Start Page
925
End Page
930
DOI
10.1021/ml3001962

Anti-AIDS agents 90. novel C-28 modified bevirimat analogues as potent HIV maturation inhibitors

In a continuing study of bevirimat (2), the anti-HIV-maturation clinical trials agent, 28 new betulinic acid (BA, 1) derivatives were designed and synthesized. Among these compounds, 17, with a C-28 MEM ester moiety, and 22, with a C-28 ethyl hexanoate, increased the anti-HIV replication activity compared with 2 by 2-fold while compounds 40, 41, 48, and 49, with C-28 piperazine or piperidine amide substitutions, increased the activity by 3- to 15-fold. The best new compound, 41, exhibited an anti-HIV IC50 of 0.0059 μM compared with 0.087 μM for 2. All of the active compounds showed only antimaturation effects, as confirmed by TZM-bl assay, in blocking the HIV replication. The results suggest that proper C-28 substitutions can further enhance the antimaturation activity of 2 without any antientry effects. Thus, 41 may serve as a promising new lead for development of anti-AIDS clinical trial candidates. © 2012 American Chemical Society.

Authors
Qian, K; Bori, ID; Chen, C-H; Huang, L; Lee, K-H
MLA Citation
Qian, K, Bori, ID, Chen, C-H, Huang, L, and Lee, K-H. "Anti-AIDS agents 90. novel C-28 modified bevirimat analogues as potent HIV maturation inhibitors." Journal of Medicinal Chemistry 55.18 (2012): 8128-8136.
PMID
22978745
Source
scival
Published In
Journal of Medicinal Chemistry
Volume
55
Issue
18
Publish Date
2012
Start Page
8128
End Page
8136
DOI
10.1021/jm301040s

Blocking HIV-1 entry by a gp120 surface binding inhibitor

We report the mode of action of a proteomimetic compound that binds to the exterior surface of gp120 and blocks HIV-1 entry into cells. Using a one cycle time-of-addition study and antibody competition binding studies, we have determined that the compound blocks HIV-1 entry through modulation of key protein-protein interactions mediated by gp120. The compound exhibits anti-HIV-1 replication activities against several pseudotype viruses derived from primary isolates and the resistant strains isolated from existing drug candidates with equal potency. Together, these data provide evidence that the proteomimetic compound represents a novel class of HIV-1 viral entry inhibitor that functions through protein surface recognition in analogy to an antibody. © 2012 Elsevier Ltd. All rights reserved.

Authors
Tsou, LK; Chen, C-H; Dutschman, GE; Cheng, Y-C; Hamilton, AD
MLA Citation
Tsou, LK, Chen, C-H, Dutschman, GE, Cheng, Y-C, and Hamilton, AD. "Blocking HIV-1 entry by a gp120 surface binding inhibitor." Bioorganic and Medicinal Chemistry Letters 22.9 (2012): 3358-3361.
PMID
22487177
Source
scival
Published In
Bioorganic & Medicinal Chemistry Letters
Volume
22
Issue
9
Publish Date
2012
Start Page
3358
End Page
3361
DOI
10.1016/j.bmcl.2012.02.079

Design and synthesis of naphthoquinone derivatives as antiproliferative agents and 20S proteasome inhibitors

Fourteen naphthoquinone derivatives (1-14) were designed based on a putative proteasome inhibitor PI-083. These compounds were synthesized and evaluated against A549, DU145, KB, and KBvin tumor cell lines. Six compounds (2, 4, 8, 9, 10, and 13) showed antiproliferative activities comparable to that of PI-083. Among them, compound 8 was confirmed as a 20S proteasome inhibitor in both in vitro and cell-based assays. These findings endorse further optimization efforts based on this structural phenotype to develop potential anticancer drug candidates. © 2012 Elsevier Ltd. All rights reserved.

Authors
Xu, K; Xiao, Z; Tang, YB; Huang, L; Chen, C-H; Ohkoshi, E; Lee, K-H
MLA Citation
Xu, K, Xiao, Z, Tang, YB, Huang, L, Chen, C-H, Ohkoshi, E, and Lee, K-H. "Design and synthesis of naphthoquinone derivatives as antiproliferative agents and 20S proteasome inhibitors." Bioorganic and Medicinal Chemistry Letters 22.8 (2012): 2772-2774.
PMID
22437113
Source
scival
Published In
Bioorganic & Medicinal Chemistry Letters
Volume
22
Issue
8
Publish Date
2012
Start Page
2772
End Page
2774
DOI
10.1016/j.bmcl.2012.02.086

Anti-AIDS agents 88. Anti-HIV conjugates of betulin and betulinic acid with AZT prepared via click chemistry

In the present study, a new strategy to link AZT with betulin/betulinic acid (BA) by click chemistry was designed and achieved. This conjugation via a triazole linkage offers a new direction for the modification of anti-HIV triterpenes. Click chemistry provides an easy and productive way for linking two molecules, even when one of them is a large natural product. Among the newly synthesized conjugates, compounds 15 and 16 showed potent anti-HIV activity with EC 50 values of 0.067 and 0.10 μM, respectively, which are comparable to that of AZT (EC 50: 0.10 μM) in the same assay. © 2011 Elsevier Inc. All rights reserved.

Authors
Bori, ID; Hung, H-Y; Qian, K; Chen, C-H; Morris-Natschke, SL; Lee, K-H
MLA Citation
Bori, ID, Hung, H-Y, Qian, K, Chen, C-H, Morris-Natschke, SL, and Lee, K-H. "Anti-AIDS agents 88. Anti-HIV conjugates of betulin and betulinic acid with AZT prepared via click chemistry." Tetrahedron Letters 53.15 (2012): 1987-1989.
PMID
22711941
Source
scival
Published In
Tetrahedron Letters
Volume
53
Issue
15
Publish Date
2012
Start Page
1987
End Page
1989
DOI
10.1016/j.tetlet.2012.02.022

Optimization of 2,4-diarylanilines as non-nucleoside HIV-1 reverse transcriptase inhibitors

The current optimization of 2,4-diarylaniline analogs (DAANs) on the central phenyl ring provided a series of new active DAAN derivatives 9a-9e, indicating an accessible modification approach that could improve anti-HIV potency against wild-type and resistant strains, aqueous solubility, and metabolic stability. A new compound 9e not only exhibited extremely high potency against wild-type virus (EC 50 0.53 nM) and several resistant viral strains (EC 50 0.36-3.9 nM), but also showed desirable aqueous solubility and metabolic stability, which were comparable or better than those of the anti-HIV-1 drug TMC278 (2). Thus, new compound 9e might be a potential drug candidate for further development of novel next-generation NNRTIs. © 2011 Elsevier Ltd. All rights reserved.

Authors
Sun, L-Q; Qin, B; Huang, L; Qian, K; Chen, C-H; Lee, K-H; Xie, L
MLA Citation
Sun, L-Q, Qin, B, Huang, L, Qian, K, Chen, C-H, Lee, K-H, and Xie, L. "Optimization of 2,4-diarylanilines as non-nucleoside HIV-1 reverse transcriptase inhibitors." Bioorganic and Medicinal Chemistry Letters 22.7 (2012): 2376-2379.
PMID
22406117
Source
scival
Published In
Bioorganic & Medicinal Chemistry Letters
Volume
22
Issue
7
Publish Date
2012
Start Page
2376
End Page
2379
DOI
10.1016/j.bmcl.2012.02.055

Anti-AIDS agents 85. Design, synthesis, and evaluation of 1R,2R-dicamphanoyl-3,3-dimethyldihydropyrano-[2,3-c]xanthen-7(1H)-one (DCX) derivatives as novel anti-HIV agents

In this study, 1R,2R-dicamphanoyl-3,3-dimethydihydropyrano[2,3-c]xanthen- 7(1H)-one (DCX) derivatives were designed and synthesized as novel anti-HIV agents against both wild-type and non-nucleoside reverse transcriptase (RT) inhibitor-resistant HIV-1 (RTMDR-1) strains. Twenty-four DCX analogs (6-29) were synthesized and evaluated against the non-drug-resistant HIV-1 NL4-3 strain, and selected analogs were also screened for their ability to inhibit the RTMDR-1 strain. Compared with the control 2-ethyl-3′,4′-di-O-(-)- camphanoyl-2′,2′-dimethyldihydropyrano[2,3-f]chromone (2-EDCP, 2), one of the best anti-HIV coumarin derivatives in our prior study, three DCX compounds (7, 12, and 22) showed better activity against both HIV strains with an EC 50 range of 0.062-0.081 μM, and five additional compounds (8, 11, 16, 18, and 21) exhibited comparable anti-HIV potency. Six DCX analogs (7, 11-12, 18, and 21-22) also showed enhanced selectivity index (SI) values in comparison to the control. Structure-activity relationship (SAR) information suggested that the extended conjugated system of the pyranoxanthone skeleton facilitates the interaction of the small DCX molecule within the viral binding pocket, consequently leading to enhanced anti-HIV activity and selectivity. Compared to DCP compounds, DCX analogs are a more promising new class of anti-HIV agents. © 2011 Elsevier Masson SAS. All rights reserved.

Authors
Zhou, T; Shi, Q; Chen, C-H; Huang, L; Ho, P; Morris-Natschke, SL; Lee, K-H
MLA Citation
Zhou, T, Shi, Q, Chen, C-H, Huang, L, Ho, P, Morris-Natschke, SL, and Lee, K-H. "Anti-AIDS agents 85. Design, synthesis, and evaluation of 1R,2R-dicamphanoyl-3,3-dimethyldihydropyrano-[2,3-c]xanthen-7(1H)-one (DCX) derivatives as novel anti-HIV agents." European Journal of Medicinal Chemistry 47.1 (2012): 86-96.
PMID
22063755
Source
scival
Published In
European Journal of Medicinal Chemistry
Volume
47
Issue
1
Publish Date
2012
Start Page
86
End Page
96
DOI
10.1016/j.ejmech.2011.10.025

Design, synthesis, and preclinical evaluations of novel 4-substituted 1,5-diarylanilines as potent HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI) drug candidates

Twenty-one new 4-substituted diarylaniline compounds (DAANs) (series 13, 14, and 15) were designed, synthesized, and evaluated against wildtype and drug resistant HIV-1 viral strains. As a result, approximately a dozen new DAANs showed high potency with low nano- to subnanomolar EC50 values ranging from 0.2 to 10 nM. The three most promising compounds 14e, 14h, and 15h exhibited high potency against wild-type and drug-resistant viral strains with EC50 values at the subnanomolar level (0.29-0.87 nM) and were comparable to or more potent than the new NNRTI drug riplivirine (2) in the same assays. Druglike physicochemical property assessments revealed that the most active DAANs (EC50 < 10 nM) have better aqueous solubility (>1-90 μg/mL at pH 7.4 and pH 2) and metabolic stability in vitro than 2, as well as desirable log P values (<5) and polar surface areas (PSA) (<140 Å2). These promising results warrant further development of this novel compound class as potential potent anti-AIDS clinical trial candidates. © 2012 American Chemical Society.

Authors
Sun, L-Q; Zhu, L; Qian, K; Qin, B; Huang, L; Chen, CH; Lee, K-H; Xie, L
MLA Citation
Sun, L-Q, Zhu, L, Qian, K, Qin, B, Huang, L, Chen, CH, Lee, K-H, and Xie, L. "Design, synthesis, and preclinical evaluations of novel 4-substituted 1,5-diarylanilines as potent HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI) drug candidates." Journal of Medicinal Chemistry 55.16 (2012): 7219-7229.
PMID
22856541
Source
scival
Published In
Journal of Medicinal Chemistry
Volume
55
Issue
16
Publish Date
2012
Start Page
7219
End Page
7229
DOI
10.1021/jm3007678

The role of dynamin in HIV type 1 Env-mediated cell-cell fusion.

HIV-1 envelope glycoproteins are the key viral proteins that mediate HIV-1 entry and cell-cell fusion. In contrast to HIV-1 entry, the mechanism of HIV-1 Env-mediated cell-cell fusion is relatively unclear. This study demonstrated that dynasore, a dynamin inhibitor, suppressed HIV-1 Env-mediated cell-cell fusion. Dynasore sensitivity of HIV-1 Env-mediated cell-cell fusion varied depending on the viral strains. Results from testing a panel of gp41 cytoplasmic tail truncation mutants suggested that the gp41 cytoplasmic tail might play a role in dynasore sensitivity. HIV-1 Env-mediated cell-cell fusion could also be suppressed by a dynamin dominant-negative mutant DNM2(K44A). In summary, these results suggested that dynamin 2 might play a role in HIV-1 Env-mediated cell-cell fusion.

Authors
Lai, W; Huang, L; Ho, P; Montefiori, D; Chen, C-H
MLA Citation
Lai, W, Huang, L, Ho, P, Montefiori, D, and Chen, C-H. "The role of dynamin in HIV type 1 Env-mediated cell-cell fusion." AIDS Res Hum Retroviruses 27.9 (September 2011): 1013-1017.
PMID
21338326
Source
pubmed
Published In
AIDS Research and Human Retroviruses
Volume
27
Issue
9
Publish Date
2011
Start Page
1013
End Page
1017
DOI
10.1089/AID.2010.0259

Synthesis and proteasome inhibition of lithocholic acid derivatives.

A new class of proteasome inhibitors was synthesized using lithocholic acid as a scaffold. Modification at the C-3 position of lithocholic acid with a series of acid acyl groups yielded compounds with a range of potency on proteasome inhibition. Among them, the phenylene diacetic acid hemiester derivative (13) displayed the most potent proteasome inhibition with IC(50) = 1.9 μM. Enzyme kinetic analysis indicates that these lithocholic acid derivatives are noncompetitive inhibitors of the proteasome.

Authors
Dang, Z; Lin, A; Ho, P; Soroka, D; Lee, K-H; Huang, L; Chen, C-H
MLA Citation
Dang, Z, Lin, A, Ho, P, Soroka, D, Lee, K-H, Huang, L, and Chen, C-H. "Synthesis and proteasome inhibition of lithocholic acid derivatives." Bioorg Med Chem Lett 21.7 (April 1, 2011): 1926-1928.
PMID
21388808
Source
pubmed
Published In
Bioorganic & Medicinal Chemistry Letters
Volume
21
Issue
7
Publish Date
2011
Start Page
1926
End Page
1928
DOI
10.1016/j.bmcl.2011.02.041

Oxathiazole-2-one derivative of bortezomib: Synthesis, stability and proteasome inhibition activity

Oxathiazole-2-one is a new candidate for proteasome inhibition which has not been widely explored. We describe herein the synthesis and characterization of a new oxathiazole-2-one derived from the dipeptide backbone of Bortezomib. We found that this new oxathiazole-2-one compound 1 is modestly active against the human 20S proteasome, but surprisingly has no significant activity against the M. tuberculosis proteasome. Additionally, the compound has improved aqueous stability compared to previously reported oxathiazole-2-one compounds. Molecular docking analyses provided information on the structural basis of the observed disparity between the human and mycobacterium proteasomes inhibitory activity of compound 1. © 2011 The Royal Society of Chemistry.

Authors
Gryder, BE; Guerrant, W; Chen, CH; Oyelere, AK
MLA Citation
Gryder, BE, Guerrant, W, Chen, CH, and Oyelere, AK. "Oxathiazole-2-one derivative of bortezomib: Synthesis, stability and proteasome inhibition activity." MedChemComm 2.11 (2011): 1083-1086.
Source
scival
Published In
MedChemComm
Volume
2
Issue
11
Publish Date
2011
Start Page
1083
End Page
1086
DOI
10.1039/c1md00208b

Picomolar dichotomous activity of gnidimacrin against HIV-1.

Highly active antiretroviral therapy (HAART) has offered a promising approach for controlling HIV-1 replication in infected individuals. However, with HARRT, HIV-1 is suppressed rather than eradicated due to persistence of HIV-1 in latent viral reservoirs. Thus, purging the virus from latent reservoirs is an important strategy toward eradicating HIV-1 infection. In this study, we discovered that the daphnane diterpene gnidimacrin, which was previously reported to have potent anti-cancer cell activity, activated HIV-1 replication and killed persistently-infected cells at picomolar concentrations. In addition to its potential to purge HIV-1 from latently infected cells, gnidimacrin potently inhibited a panel of HIV-1 R5 virus infection of peripheral blood mononuclear cells (PBMCs) at an average concentration lower than 10 pM. In contrast, gnidimacrin only partially inhibited HIV-1 ×4 virus infection of PBMCs. The strong anti-HIV-1 R5 virus activity of gnidimacrin was correlated with its effect on down-regulation of the HIV-1 coreceptor CCR5. The anti-R5 virus activity of gnidimacrin was completely abrogated by a selective protein kinase C beta inhibitor enzastaurin, which suggests that protein kinase C beta plays a key role in the potent anti-HIV-1 activity of gnidimacrin in PBMCs. In summary, these results suggest that gnidimacrin could activate latent HIV-1, specifically kill HIV-1 persistently infected cells, and inhibit R5 viruses at picomolar concentrations.

Authors
Huang, L; Ho, P; Yu, J; Zhu, L; Lee, K-H; Chen, C-H
MLA Citation
Huang, L, Ho, P, Yu, J, Zhu, L, Lee, K-H, and Chen, C-H. "Picomolar dichotomous activity of gnidimacrin against HIV-1." PLoS One 6.10 (2011): e26677-.
PMID
22039528
Source
pubmed
Published In
PloS one
Volume
6
Issue
10
Publish Date
2011
Start Page
e26677
DOI
10.1371/journal.pone.0026677

Anti-AIDS agents 86. Synthesis and anti-HIV evaluation of 2′,3′-seco-3′-nor DCP and DCK analogues

In a continuing study of novel anti-HIV agents with drug-like structures and properties, 30 1′-O-, 1′-S-, 4′-O- and 4′-substituted-2′,3′-seco-3′-nor DCP and DCK analogues (8-37) were designed and synthesized. All newly synthesized seco-compounds were screened against HIV-1 NL4-3 and a multiple reverse transcriptase (RT) inhibitor-resistant (RTMDR) strain in the TZM-bl cell line, using seco-DCK (7) and 2-ethyl-DCP (4) as controls. Several compounds (14, 18, 19, 22-24, and 32) exhibited potent anti-HIV activity with EC 50 values ranging from 0.93 to 1.93 μM and therapeutic index (TI) values ranging from 20 to 39. 1′-O-Isopropoxy-2′,3′-seco-3′-nor-DCP (12) showed the greatest potency among the newly synthesized compounds with EC 50 values of 0.47 and 0.88 μM, and TI of 96 and 51, respectively, against HIV-1 NL4-3 and RTMDR strains. The seco-compounds exhibited better chemical stability in acidic conditions compared with DCP and DCK compounds. Overall, the results suggested that seco-DCP analogues with simplified structures may be more favorable for development as novel anti-HIV candidates. © 2011 Elsevier Masson SAS. All rights reserved.

Authors
Chen, Y; Cheng, M; Liu, F-Q; Xia, P; Qian, K; Yu, D; Xia, Y; Yang, Z-Y; Chen, C-H; Morris-Natschke, SL; Lee, K-H
MLA Citation
Chen, Y, Cheng, M, Liu, F-Q, Xia, P, Qian, K, Yu, D, Xia, Y, Yang, Z-Y, Chen, C-H, Morris-Natschke, SL, and Lee, K-H. "Anti-AIDS agents 86. Synthesis and anti-HIV evaluation of 2′,3′-seco-3′-nor DCP and DCK analogues." European Journal of Medicinal Chemistry 46.10 (2011): 4924-4936.
PMID
21864952
Source
scival
Published In
European Journal of Medicinal Chemistry
Volume
46
Issue
10
Publish Date
2011
Start Page
4924
End Page
4936
DOI
10.1016/j.ejmech.2011.07.051

Anti-AIDS agents 87. New bio-isosteric dicamphanoyl-dihydropyranochromone (DCP) and dicamphanoyl-khellactone (DCK) analogues with potent anti-HIV activity

Six 3′R,4′R-di-O-(S)-camphanoyl-2′,2′- dimethyldihydropyrano[2,3-f]chromone (DCP) and two 3′R,4′R-di-O-(S)- camphanoyl-(+)-cis-khellactone (DCK) derivatives were designed, synthesized, and evaluated for inhibition of HIV-1 NL4-3 replication in TZM-bl cells. 2-Ethyl-2′-monomethyl-1′-oxa- and -1′-thia-DCP (5a, 6a), as well as 2-ethyl-1′-thia-DCP (7a) exhibited potent anti-HIV activity with EC 50 values of 30, 38 and 54 nM and therapeutic indexes of 152.6, 48.0 and 100.0, respectively, which were better than or comparable to those of the lead compound 2-ethyl-DCP in the same assay. 4-Methyl-1′-thia-DCK (8a) also showed significant inhibitory activity with an EC 50 of 128 nM and TI of 237.9. © 2011 Elsevier Ltd. All rights reserved.

Authors
Liu, H-S; Xu, S-Q; Cheng, M; Chen, Y; Xia, P; Qian, K; Xia, Y; Yang, Z-Y; Chen, C-H; Morris-Natschke, SL; Lee, K-H
MLA Citation
Liu, H-S, Xu, S-Q, Cheng, M, Chen, Y, Xia, P, Qian, K, Xia, Y, Yang, Z-Y, Chen, C-H, Morris-Natschke, SL, and Lee, K-H. "Anti-AIDS agents 87. New bio-isosteric dicamphanoyl-dihydropyranochromone (DCP) and dicamphanoyl-khellactone (DCK) analogues with potent anti-HIV activity." Bioorganic and Medicinal Chemistry Letters 21.19 (2011): 5831-5834.
PMID
21871800
Source
scival
Published In
Bioorganic & Medicinal Chemistry Letters
Volume
21
Issue
19
Publish Date
2011
Start Page
5831
End Page
5834
DOI
10.1016/j.bmcl.2011.07.105

New betulinic acid derivatives as potent proteasome inhibitors

In this study, 22 new betulinic acid (BA) derivatives were synthesized and tested for their inhibition of the chymotrypsin-like activity of 20S proteasome. From the SAR study, we concluded that the C-3 and C-30 positions are the pharmacophores for increasing the proteasome inhibition effects, and larger lipophilic or aromatic side chains are favored at these positions. Among the BA derivatives tested, compounds 13, 20, and 21 showed the best proteasome inhibition activity with IC 50 values of 1.42, 1.56, and 1.80 μM, respectively, which are three to fourfold more potent than the proteasome inhibition controls LLM-F and lactacystin. © 2011 Elsevier Ltd. All rights reserved.

Authors
Qian, K; Kim, S-Y; Hung, H-Y; Huang, L; Chen, C-H; Lee, K-H
MLA Citation
Qian, K, Kim, S-Y, Hung, H-Y, Huang, L, Chen, C-H, and Lee, K-H. "New betulinic acid derivatives as potent proteasome inhibitors." Bioorganic and Medicinal Chemistry Letters 21.19 (2011): 5944-5947.
PMID
21856154
Source
scival
Published In
Bioorganic & Medicinal Chemistry Letters
Volume
21
Issue
19
Publish Date
2011
Start Page
5944
End Page
5947
DOI
10.1016/j.bmcl.2011.07.072

Synthesis of new 2′-deoxy-2′-fluoro-4′-azido nucleoside analogues as potent anti-HIV agents

We prepared 1-(4′-azido-2′-deoxy-2′-fluoro-β-d- arabinofuranosyl)cytosine (10) and its hydrochloride salt (11) as potential antiviral agents based on the favorable antiviral profiles of 4′-substituted nucleosides. Compounds 10 and 11 were synthesized from 1,3,5-O-tribenzoyl-2-deoxy-2-fluoro-d-arabinofuranoside in multiple steps, and their structures were unequivocally established by IR, 1H NMR, 13C NMR, and 19F NMR spectroscopy, HRMS, and X-ray crystallography. Compounds 10 and 11 exhibited potent anti-HIV-1 activity (EC 50: 0.3 and 0.13 nM, respectively) without significant cytotoxicity in concentrations up to 100 μM. Compound 11 exhibited extremely potent anti-HIV activity against NL4-3 (wild-type), NL4-3 (K101E), and RTMDR viral strains, with EC 50 values of 0.086, 0.15, and 0.11 nM, respectively. Due to the high potency of 11, it was also screened against an NIH Reagent Program NRTI-resistant virus panel containing eleven mutated viral strains and for cytotoxicity against six different human cell lines. The results of this screening indicated that 11 is a novel NRTI that could be developed as an anti-AIDS clinical trial candidate to overcome drug-resistance issues. © 2011 Elsevier Masson SAS. All rights reserved.

Authors
Wang, Q; Hu, W; Wang, S; Pan, Z; Tao, L; Guo, X; Qian, K; Chen, C-H; Lee, K-H; Chang, J
MLA Citation
Wang, Q, Hu, W, Wang, S, Pan, Z, Tao, L, Guo, X, Qian, K, Chen, C-H, Lee, K-H, and Chang, J. "Synthesis of new 2′-deoxy-2′-fluoro-4′-azido nucleoside analogues as potent anti-HIV agents." European Journal of Medicinal Chemistry 46.9 (2011): 4178-4183.
PMID
21745701
Source
scival
Published In
European Journal of Medicinal Chemistry
Volume
46
Issue
9
Publish Date
2011
Start Page
4178
End Page
4183
DOI
10.1016/j.ejmech.2011.06.020

Stelleralides A-C, novel potent anti-HIV daphnane-type diterpenoids from stellera chamaejasm e L.

Three novel 1-alkyldaphnane-type diterpenes, stelleralides A-C (4-6), and five known compounds were isolated from the roots of Stellera chamaejasme L. The structures of 4-6 were elucidated by extensive spectroscopic analyses. Several isolated compounds showed potent anti-HIV activity. Compound 4 showed extremely potent anti-HIV activity (EC90 0.40 nM) with the lowest cytotoxicity (IC50 4.3 μM) and appears to be a promising compound for development into anti-AIDS clinical trial candidates. © 2011 American Chemical Society.

Authors
Asada, Y; Sukemori, A; Watanabe, T; Malla, KJ; Yoshikawa, T; Li, W; Koike, K; Chen, C-H; Akiyama, T; Qian, K; Nakagawa-Goto, K; Morris-Natschke, SL; Lee, K-H
MLA Citation
Asada, Y, Sukemori, A, Watanabe, T, Malla, KJ, Yoshikawa, T, Li, W, Koike, K, Chen, C-H, Akiyama, T, Qian, K, Nakagawa-Goto, K, Morris-Natschke, SL, and Lee, K-H. "Stelleralides A-C, novel potent anti-HIV daphnane-type diterpenoids from stellera chamaejasm e L." Organic Letters 13.11 (2011): 2904-2907.
PMID
21561135
Source
scival
Published In
Organic Letters
Volume
13
Issue
11
Publish Date
2011
Start Page
2904
End Page
2907
DOI
10.1021/ol200889s

Design, synthesis and evaluation of novel 2H-1, 4-benzodiazepine-2-ones as inhibitors of HIV-1 transcription

HIV-1 trans-activator of transcription (Tat) plays a critical role in HIV-1 transcription. Based on the β-turn motif present in HIV-1 Tat, a series of novel benzodiazepine analogs were designed as β-turn mimetics and prepared from p-chloro-nitrobenzene/2-phenylacetonitrile, p-toluidine/benzoyl chloride, or (Z)-7-nitro-5-phenyl-1H-benzo[e][1, 4]diazepin-2(3H)-one (nitrazepam) through different synthetic routes. Preliminary biological evaluation indicated that compound 30 exhibited inhibitory activity on HIV-1 tat-mediated LTR transcription with EC50 of 25.0 μmol·L-1 and showed no obvious cytotoxic effects on TZM-B1 cells under the concentration of 100 μmol·L-1.

Authors
Tang, Y-B; Zhang, C-M; Fang, C; Hu, C; Huang, L; Chen, C-H; Xiao, Z-Y
MLA Citation
Tang, Y-B, Zhang, C-M, Fang, C, Hu, C, Huang, L, Chen, C-H, and Xiao, Z-Y. "Design, synthesis and evaluation of novel 2H-1, 4-benzodiazepine-2-ones as inhibitors of HIV-1 transcription." Yaoxue Xuebao 46.6 (2011): 688-694.
PMID
21882530
Source
scival
Published In
Yao xue xue bao = Acta pharmaceutica Sinica
Volume
46
Issue
6
Publish Date
2011
Start Page
688
End Page
694

Design, synthesis and structure-activity relationships of novel dicamphanoyl-2 ',2 '-dimethyldihydropyranochromone (DCP) analogs as potent anti-HIV agents

Authors
Zhou, T; Chen, C-H; Shi, Q; Huang, L; Ho, P; Lee, K-H
MLA Citation
Zhou, T, Chen, C-H, Shi, Q, Huang, L, Ho, P, and Lee, K-H. "Design, synthesis and structure-activity relationships of novel dicamphanoyl-2 ',2 '-dimethyldihydropyranochromone (DCP) analogs as potent anti-HIV agents." August 22, 2010.
Source
wos-lite
Published In
ACS National Meeting Book of Abstracts
Volume
240
Publish Date
2010

HIV entry inhibitors: progress in development and application.

This review discusses recent progress in the development of anti-HIV agents, with emphasis on small molecule HIV-1 entry inhibitors. The entry inhibitors primarily target HIV-1 envelope glycoproteins or the cellular receptors, CD4 and chemokine receptors. Two of the entry inhibitors, enfuvirtide and maraviroc, have been approved by the US FDA for AIDS therapy. The drug resistance associated with some of the entry inhibitors will also be discussed.

Authors
Lai, W-H; Huang, L; Chen, C-H
MLA Citation
Lai, W-H, Huang, L, and Chen, C-H. "HIV entry inhibitors: progress in development and application." Yao Xue Xue Bao 45.2 (February 2010): 131-140. (Review)
PMID
21348414
Source
pubmed
Published In
Yao xue xue bao = Acta pharmaceutica Sinica
Volume
45
Issue
2
Publish Date
2010
Start Page
131
End Page
140

Design, synthesis, and evaluation of diarylpyridines and diarylanilines as potent non-nucleoside HIV-1 reverse transcriptase inhibitors

On the basis of the structures and activities of our previously identified non-nucleoside reverse transcriptase inhibitors (NNRTIs), we designed and synthesized two sets of derivatives, diarylpyridines (A) and diarylanilines (B), and tested their anti-HIV-1 activity against infection by HIV-1 NL4-3 and IIIB in TZM-bl and MT-2 cells, respectively. The results showed that most compounds exhibited potent anti-HIV-1 activity with low nanomolar EC50 values, and some of them, such as 13m, 14c, and 14e, displayed high potency with subnanomolar EC50 values, which were more potent than etravirine (TMC125, 1) in the same assays. Notably, these compounds were also highly effective against infection by multi-RTI-resistant strains, suggesting a high potential to further develop these compounds as a novel class of NNRTIs with improved antiviral efficacy and resistance profile. © 2010 American Chemical Society.

Authors
Tian, X; Qin, B; Wu, Z; Wang, X; Lu, H; Morris-Natschke, SL; Chen, CH; Jiang, S; Lee, K-H; Xie, L
MLA Citation
Tian, X, Qin, B, Wu, Z, Wang, X, Lu, H, Morris-Natschke, SL, Chen, CH, Jiang, S, Lee, K-H, and Xie, L. "Design, synthesis, and evaluation of diarylpyridines and diarylanilines as potent non-nucleoside HIV-1 reverse transcriptase inhibitors." Journal of Medicinal Chemistry 53.23 (2010): 8287-8297.
Website
http://hdl.handle.net/10161/4059
PMID
21049929
Source
scival
Published In
Journal of Medicinal Chemistry
Volume
53
Issue
23
Publish Date
2010
Start Page
8287
End Page
8297
DOI
10.1021/jm100738d

Anti-AIDS agents 79. Design, synthesis, molecular modeling and structure-activity relationships of novel dicamphanoyl-2′,2′- dimethyldihydropyranochromone (DCP) analogs as potent anti-HIV agents

In a continued study, 23 3′R,4′R-di-O-(-)-camphanoyl-2′, 2′-dimethyldihydropyrano[2,3-f]chromone (DCP) derivatives (5-27) were synthesized, and screened for anti-HIV activity against both a non-drug-resistant NL4-3 strain and multiple reverse transcriptase (RT) inhibitor-resistant (RTMDR-1) strain, using 2-EDCP (4) and 2-MDCP (35) as controls. New DCP analogs 5, 9, 14, and 22 exhibited potent anti-HIV activity against HIVNL4-3 with EC50 and therapeutic index (TI) values ranging from 0.036 μM to 0.14 μM and from 110 to 420, respectively. Compounds 5 and 9 also exhibited good activity against RTMDR-1 (EC50 0.049 and 0.054 μM; TI 310 and 200, respectively), and were twofold more potent than the leads 4 and 35 (EC50 0.11 and 0.19 μM; TI 60 and 58, respectively). Evaluation of water solubility showed that 5 and 22 were 5-10 times more water soluble than 4. Quantitative structure-activity relationship (QSAR) modeling results were first performed on this compound type, and the models should aid in design of future anti-HIV DCP analogs and potential clinical drug candidates. © 2010 Elsevier Ltd. All rights reserved.

Authors
Zhou, T; Shi, Q; Chen, C-H; Zhu, H; Huang, L; Ho, P; Lee, K-H
MLA Citation
Zhou, T, Shi, Q, Chen, C-H, Zhu, H, Huang, L, Ho, P, and Lee, K-H. "Anti-AIDS agents 79. Design, synthesis, molecular modeling and structure-activity relationships of novel dicamphanoyl-2′,2′- dimethyldihydropyranochromone (DCP) analogs as potent anti-HIV agents." Bioorganic and Medicinal Chemistry 18.18 (2010): 6678-6689.
PMID
20728367
Source
scival
Published In
Bioorganic & Medicinal Chemistry
Volume
18
Issue
18
Publish Date
2010
Start Page
6678
End Page
6689
DOI
10.1016/j.bmc.2010.07.065

Conjugates of betulin derivatives with AZT as potent anti-HIV agents

Fourteen novel conjugates of 3,28-di-O-acylbetulins with AZT were prepared as anti-HIV agents, based on our previously reported potent anti-HIV triterpene leads, including 3-O-acyl and 3,28-di-O-acylbetulins. Nine of the conjugates (49-53, 55, 56, 59, and 60) exhibited potent anti-HIV activity at the submicromolar level, with EC50 values ranging from 0.040 to 0.098 μM in HIV-1NL4-3 infected MT-4 cells. These compounds were equipotent or more potent than 3-O-(3′,3′-dimethylsuccinyl)betulinic acid (2), which is currently in Phase IIb anti-AIDS clinical trial. © 2010 Elsevier Ltd. All rights reserved.

Authors
Xiong, J; Kashiwada, Y; Chen, C-H; Qian, K; Morris-Natschke, SL; Lee, K-H; Takaishi, Y
MLA Citation
Xiong, J, Kashiwada, Y, Chen, C-H, Qian, K, Morris-Natschke, SL, Lee, K-H, and Takaishi, Y. "Conjugates of betulin derivatives with AZT as potent anti-HIV agents." Bioorganic and Medicinal Chemistry 18.17 (2010): 6451-6469.
PMID
20673723
Source
scival
Published In
Bioorganic & Medicinal Chemistry
Volume
18
Issue
17
Publish Date
2010
Start Page
6451
End Page
6469
DOI
10.1016/j.bmc.2010.06.092

Diarylaniline derivatives as a distinct class of HIV-1 non-nucleoside reverse transcriptase inhibitors

By using structure-based drug design and isosteric replacement, diarylaniline and 1,5-diarylbenzene-1,2-diamine derivatives were synthesized and evaluated against wild type HIV-1 and drug-resistant viral strains, resulting in the discovery of diarylaniline derivatives as a distinct class of next-generation HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI) agents. The most promising compound 37 showed significant EC50 values of 0.003-0.032 mn; against HIV-1 wild-type strains and of 0.005-0.604 μM against several drug-resistant strains. Current results also revealed important structure-activity relationship (SAR) conclusions for diarylanilines and strongly support our hypothesis that an NH2 group on the central benzene ring ortho to the aniline moiety is crucial for interaction with K101 of the NNRTI binding site in HIV-1 RT, likely by forming H-bonds with K101. Furthermore, molecular modeling studies with molecular mechanism/general Born surface area (MM/GBSA) technology demonstrated the rationality of our hypothesis. © 2010 American Chemical Society.

Authors
Qin, B; Jiang, X; Lu, H; Tian, X; Barbault, F; Huang, L; Qian, K; Chen, C-H; Huang, R; Jiang, S; Lee, K-H; Xie, L
MLA Citation
Qin, B, Jiang, X, Lu, H, Tian, X, Barbault, F, Huang, L, Qian, K, Chen, C-H, Huang, R, Jiang, S, Lee, K-H, and Xie, L. "Diarylaniline derivatives as a distinct class of HIV-1 non-nucleoside reverse transcriptase inhibitors." Journal of Medicinal Chemistry 53.13 (2010): 4906-4916.
Website
http://hdl.handle.net/10161/4057
PMID
20527972
Source
scival
Published In
Journal of Medicinal Chemistry
Volume
53
Issue
13
Publish Date
2010
Start Page
4906
End Page
4916
DOI
10.1021/jm1002952

Synthesis and anti-HIV activity of 2′-deoxy-2′-fluoro-4′-C-ethynyl nucleoside analogs

Based on the favorable antiviral profiles of 4′-substituted nucleosides, novel 1-(2′-deoxy-2′-fluoro-4′-C-ethynyl-β-d-arabinofuranosyl)-uracil (1a), -thymine (1b), and -cytosine (2) analogs were synthesized. Compounds 1b and 2 exhibited potent anti-HIV-1 activity with IC 50 values of 86 and 1.34 nM, respectively, without significant cytotoxicity. Compound 2 was 35-fold more potent than AZT against wild-type virus, and also retained nanomolar antiviral activity against resistant strains, NL4-3 (K101E) and RTMDR. Thus, 2 merits further development as a novel NRTI drug. © 2010 Elsevier Ltd. All rights reserved.

Authors
Wang, Q; Li, Y; Song, C; Qian, K; Chen, C-H; Lee, K-H; Chang, J
MLA Citation
Wang, Q, Li, Y, Song, C, Qian, K, Chen, C-H, Lee, K-H, and Chang, J. "Synthesis and anti-HIV activity of 2′-deoxy-2′-fluoro-4′-C-ethynyl nucleoside analogs." Bioorganic and Medicinal Chemistry Letters 20.14 (2010): 4053-4056.
PMID
20542430
Source
scival
Published In
Bioorganic & Medicinal Chemistry Letters
Volume
20
Issue
14
Publish Date
2010
Start Page
4053
End Page
4056
DOI
10.1016/j.bmcl.2010.05.090

Anti-AIDS agents 82: Synthesis of seco-(3′R,4′R)-3′,4′-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) derivatives as novel anti-HIV agents

Thirteen novel seco-DCK analogs (4-16) with several new skeletons were designed, synthesized and screened for in vitro anti-HIV-1 activity. Among them, three compounds (5, 13, and 16) showed moderate activity, and compound 9 exhibited the best activity with an EC50 value of 0.058 μM and a therapeutic index (TI) of 1000. The activity of 9 was better than that of 4-methyl DCK (2, EC50: 0.126 μM, TI: 301.2) in the same assay. Additionally, 9 also showed antiviral activity against a multi-RT inhibitor-resistant strain (RTMDR), which is insensitive to most DCK analogs. Compared with 2, compound 9 has a less complex structure, fewer hydrogen-bond acceptors, and a reduced log P value. Therefore, it is likely to exhibit better ADME, and appears to be a promising new lead for further development as an anti-HIV candidate. © 2010 Elsevier Ltd. All rights reserved.

Authors
Tang, J; Qian, K; Zhang, B-N; Chen, Y; Xia, P; Yu, D; Xia, Y; Yang, Z-Y; Chen, C-H; Morris-Natschke, SL; Lee, K-H
MLA Citation
Tang, J, Qian, K, Zhang, B-N, Chen, Y, Xia, P, Yu, D, Xia, Y, Yang, Z-Y, Chen, C-H, Morris-Natschke, SL, and Lee, K-H. "Anti-AIDS agents 82: Synthesis of seco-(3′R,4′R)-3′,4′-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) derivatives as novel anti-HIV agents." Bioorganic and Medicinal Chemistry 18.12 (2010): 4363-4373.
PMID
20537902
Source
scival
Published In
Bioorganic & Medicinal Chemistry
Volume
18
Issue
12
Publish Date
2010
Start Page
4363
End Page
4373
DOI
10.1016/j.bmc.2010.04.089

Anti-AIDS agents 81. design, synthesis, and structure-activity relationship study of betulinic acid and moronic acid derivatives as potent HIV maturation inhibitors

In our continuing study of triterpene derivatives as potent anti-HIV agents, different C-3 conformationally restricted betulinic acid (BA, 1) derivatives were designed and synthesized in order to explore the conformational space of the C-3 pharmacophore. 3-O-Monomethylsuccinyl-betulinic acid (MSB) analogues were also designed to better understand the contribution of the C-3′ dimethyl group of bevirimat (2), the first-in-class HIV maturation inhibitor, which is currently in phase IIb clinical trials. In addition, another triterpene skeleton, moronic acid (MA, 3), was also employed to study the influence of the backbone and the C-3 modification toward the anti-HIV activity of this compound class. This study enabled us to better understand the structure-activity relationships (SAR) of triterpene-derived anti-HIV agents and led to the design and synthesis of compound 12 (EC50: 0.0006 μM), which displayed slightly better activity than 2 as a HIV-1 maturation inhibitor. © 2010 American Chemical Society.

Authors
Qian, K; Kuo, R-Y; Chen, C-H; Huang, L; Morris-Natschke, SL; Lee, K-H
MLA Citation
Qian, K, Kuo, R-Y, Chen, C-H, Huang, L, Morris-Natschke, SL, and Lee, K-H. "Anti-AIDS agents 81. design, synthesis, and structure-activity relationship study of betulinic acid and moronic acid derivatives as potent HIV maturation inhibitors." Journal of Medicinal Chemistry 53.8 (2010): 3133-3141.
Website
http://hdl.handle.net/10161/4063
PMID
20329730
Source
scival
Published In
Journal of Medicinal Chemistry
Volume
53
Issue
8
Publish Date
2010
Start Page
3133
End Page
3141
DOI
10.1021/jm901782m

Betulinic acid derivatives as human immunodeficiency virus type 2 (HIV-2) inhibitors.

We previously reported that [[N-[3beta-hydroxyllup-20(29)-en-28-oyl]-7-aminoheptyl]carbamoyl]methane (A43D, 4) was a potent HIV-1 entry inhibitor. However, 4 was inactive against HIV-2 virus, suggesting the structural requirements for targeting these two retroviruses are different. In this study, a series of new betulinic acid derivatives were synthesized, and some of them displayed selective anti-HIV-2 activity at nanomolar concentrations. In comparison to compounds with anti-HIV-1 activity, a shorter C-28 side chain is required for optimal anti-HIV-2 activity.

Authors
Dang, Z; Lai, W; Qian, K; Ho, P; Lee, K-H; Chen, C-H; Huang, L
MLA Citation
Dang, Z, Lai, W, Qian, K, Ho, P, Lee, K-H, Chen, C-H, and Huang, L. "Betulinic acid derivatives as human immunodeficiency virus type 2 (HIV-2) inhibitors." J Med Chem 52.23 (December 10, 2009): 7887-7891.
PMID
19526990
Source
pubmed
Published In
Journal of Medicinal Chemistry
Volume
52
Issue
23
Publish Date
2009
Start Page
7887
End Page
7891
DOI
10.1021/jm9004253

Structure-activity relationship study of novel betulinic acid analogs as potent HIV maturation inhibitors

Authors
Qian, K; Nakagawa-Goto, K; Chen, C-H; Morris-Natschke, S; Lee, K-H
MLA Citation
Qian, K, Nakagawa-Goto, K, Chen, C-H, Morris-Natschke, S, and Lee, K-H. "Structure-activity relationship study of novel betulinic acid analogs as potent HIV maturation inhibitors." August 16, 2009.
Source
wos-lite
Published In
ACS National Meeting Book of Abstracts
Volume
238
Publish Date
2009

HIV-1 maturation inhibitors: An update

Authors
Dang, Z; Huang, L; Chen, C-H
MLA Citation
Dang, Z, Huang, L, and Chen, C-H. "HIV-1 maturation inhibitors: An update." Drugs of the Future 34.10 (2009): 797-797.
Source
crossref
Published In
Drugs of the future
Volume
34
Issue
10
Publish Date
2009
Start Page
797
End Page
797
DOI
10.1358/dof.2009.034.10.1428207

HIV-1 maturation inhibitors: An update

HIV-1 maturation inhibitors are compounds other than HIV-1 protease inhibitors that inhibit HIV-1 maturation. This review focuses on triterpene derivatives, as their preclinical and clinical pharmacological profiles have been relatively well studied. Among the triterpene anti-HIV-1 maturation inhibitors, the betulinic acid derivative bevirimat dimeglumine (MPC-4326, formerly PA-457) is at the most advanced stage of drug development. Myriad Pharmaceuticals acquired all rights to bevirimat from Panacos Pharmaceuticals and continues to develop it under the new name MPC-4326. Although bevirimat is a potent HIV-1 maturation inhibitor, the results from phase II clinical trials indicate that it is less effective in a subset (30-40%) of HIV-1-positive individuals due to Gag polymorphisms in the glutamine-valine-threonine (QVT) motif of spacer peptide SP1. In addition to clinical development, recent medicinal chemistry approaches to obtain HIV-1 maturation inhibitors that are more potent than bevirimat are summarized. Copyright © 2009 Prous Science, S.A.U. or its licensors. All rights reserved.

Authors
Dang, Z; Huang, L; Chen, C-H
MLA Citation
Dang, Z, Huang, L, and Chen, C-H. "HIV-1 maturation inhibitors: An update." Drugs of the Future 34.10 (2009): 797-802.
Source
scival
Published In
Drugs of the future
Volume
34
Issue
10
Publish Date
2009
Start Page
797
End Page
802
DOI
10.1358/dof.2009.34.10.1428207

Discovery of diarylpyridine derivatives as novel non-nucleoside HIV-1 reverse transcriptase inhibitors

Two series (4 and 5) of diarylpyridine derivatives were designed, synthesized, and evaluated for anti-HIV-1 activity. The most promising compound, 5e, inhibited HIV-1 IIIB, NL4-3, and RTMDR1 with low nanomolar EC50 values and selectivity indexes of >10,000. The results of this study indicate that diarylpyridine can be used as a novel scaffold to derive a new class of potent NNRTIs, active against both wild-type and drug-resistant HIV-1 strains. © 2009 Elsevier Ltd.

Authors
Tian, X; Qin, B; Lu, H; Lai, W; Jiang, S; Lee, K-H; Chen, CH; Xie, L
MLA Citation
Tian, X, Qin, B, Lu, H, Lai, W, Jiang, S, Lee, K-H, Chen, CH, and Xie, L. "Discovery of diarylpyridine derivatives as novel non-nucleoside HIV-1 reverse transcriptase inhibitors." Bioorganic and Medicinal Chemistry Letters 19.18 (2009): 5482-5485.
PMID
19666220
Source
scival
Published In
Bioorganic & Medicinal Chemistry Letters
Volume
19
Issue
18
Publish Date
2009
Start Page
5482
End Page
5485
DOI
10.1016/j.bmcl.2009.07.080

Anti-AIDS agents. 78. Design, synthesis, metabolic stability assessment, and antiviral evaluation of novel betulinic acid derivatives as potent anti-human immunodeficiency virus (HIV) agents

In a continuing study of potent anti-HIV agents, seventeen 28,30-disubstituted betulinic acid (BA, 1) derivatives and seven novel 3,28-disubstituted BA analogues were designed, synthesized, and evaluated for in vitro antiviral activity. Among them, compound 21 showed an improved solubility and equal anti-HIV potency (EC50 = 0.09 μM) when compared to HIV entry inhibitors 3b (IC9564, (3R,4S)-N′-[N-[3β-hydroxylup-20(29)-en- 28-oyl]-8-aminooctanoyl]-4-amino-3-hydroxy-6-methylheptanoic acid) and 4 (A43-D, [[N-[3β-O-(3′,3′-dimethylsuccinyl)-lup-20(29)-en-28-oyl]-7- aminoheptyl]carbamoyl]methane). Using a cyclic secondary amine to form the C-28 amide bond increased the metabolic stability of the derivatives significantly in pooled human liver microsomes. The most potent compounds 47 and 48 displayed potent anti-HIV activity with EC50 values of 0.007 and 0.006 μM, respectively. These results are slightly better than that of bevirimat (2, 3′,3′-dimethylsuccinylbetulinic acid), which is currently in phase IIb clinical trials. Compounds 47 and 48 should serve as attractive promising leads to develop next generation, metabolically stable, 3,28-disubstituted bifunctional HIV-1 inhibitors as clinical trials candidates. © 2009 American Chemical Society.

Authors
Qian, K; Yu, D; Chen, C-H; Huang, L; Morris-Natschke, SL; Nitz, TJ; Salzwedel, K; Reddick, M; Allaway, GP; Lee, K-H
MLA Citation
Qian, K, Yu, D, Chen, C-H, Huang, L, Morris-Natschke, SL, Nitz, TJ, Salzwedel, K, Reddick, M, Allaway, GP, and Lee, K-H. "Anti-AIDS agents. 78. Design, synthesis, metabolic stability assessment, and antiviral evaluation of novel betulinic acid derivatives as potent anti-human immunodeficiency virus (HIV) agents." Journal of Medicinal Chemistry 52.10 (2009): 3248-3258.
PMID
19388685
Source
scival
Published In
Journal of Medicinal Chemistry
Volume
52
Issue
10
Publish Date
2009
Start Page
3248
End Page
3258
DOI
10.1021/jm900136j

Proteasome regulators: activators and inhibitors.

This mini review covers the drug discovery aspect of both proteasome activators and inhibitors. The proteasome is involved in many essential cellular functions, such as regulation of cell cycle, cell differentiation, signal transduction pathways, antigen processing for appropriate immune responses, stress signaling, inflammatory responses, and apoptosis. Due to the importance of the proteasome in cellular functions, inhibition or activation of the proteasome could become a useful therapeutic strategy for a variety of diseases. Many proteasome inhibitors have been identified and can be classified into two groups according to their source: chemically synthesized small molecules and compounds derived from natural products. A successful example of development of a proteasome inhibitor as a clinically useful drug is the peptide boronate, PS341 (Bortezomib), was approved for the treatment of multiple myeloma. In contrast to proteasome inhibitors, small molecules that can activate or enhance proteasome activity are rare and are not well studied. The fact that over-expression of the cellular proteasome activator PA28 exhibited beneficial effects on the Huntington's disease neuronal model cells raised the prospect that small molecule proteasome activators could become useful therapeutics. The beneficial effect of oleuropein, a small molecule proteasome activator, on senescence of human fibroblasts also suggested that proteasome activators might have the potential to be developed into anti-aging agents.

Authors
Huang, L; Chen, CH
MLA Citation
Huang, L, and Chen, CH. "Proteasome regulators: activators and inhibitors." Curr Med Chem 16.8 (2009): 931-939. (Review)
PMID
19275603
Source
pubmed
Published In
Current medicinal chemistry
Volume
16
Issue
8
Publish Date
2009
Start Page
931
End Page
939

Synthesis and proteasome inhibition of glycyrrhetinic acid derivatives.

This study discovered that glycyrrhetinic acid inhibited the human 20S proteasome at 22.3microM. Esterification of the C-3 hydroxyl group on glycyrrhetinic acid with various carboxylic acid reagents yielded a series of analogs with marked improved potency. Among the derivatives, glycyrrhetinic acid 3-O-isophthalate (17) was the most potent compound with IC(50) of 0.22microM, which was approximately 100-fold more potent than glycyrrhetinic acid.

Authors
Huang, L; Yu, D; Ho, P; Qian, K; Lee, K-H; Chen, C-H
MLA Citation
Huang, L, Yu, D, Ho, P, Qian, K, Lee, K-H, and Chen, C-H. "Synthesis and proteasome inhibition of glycyrrhetinic acid derivatives." Bioorg Med Chem 16.14 (July 15, 2008): 6696-6701.
PMID
18562200
Source
pubmed
Published In
Bioorganic & Medicinal Chemistry
Volume
16
Issue
14
Publish Date
2008
Start Page
6696
End Page
6701
DOI
10.1016/j.bmc.2008.05.078

Betulinic acid derivatives that target gp120 and inhibit multiple genetic subtypes of human immunodeficiency virus type 1.

Betulinic acid (BA) derivatives can inhibit human immunodeficiency virus type 1 (HIV-1) entry or maturation depending on side chain modifications. While BA derivatives with antimaturation activity have attracted considerable interest, the anti-HIV-1 profile and molecular mechanism of BA derivatives with anti-HIV-1 entry activity (termed BA entry inhibitors) have not been well defined. In this study, we have found that two BA entry inhibitors, IC9564 and A43D, exhibited a broad spectrum of anti-HIV-1 activity. Both compounds inhibited multiple strains of HIV-1 from clades A, B, and C at submicromolar concentrations. Clade C viruses were more sensitive to the compounds than clade A and B viruses. Interestingly, IC9564 at subinhibitory concentrations could alter the antifusion activities of other entry inhibitors. IC9564 was especially potent in increasing the sensitivity of HIV-1 YU2 Env-mediated membrane fusion to the CCR5 inhibitor TAK-779. Results from this study suggest that the V3 loop of gp120 is a critical determinant for the anti-HIV-1 activity of IC9564. IC9564 escape viruses contained mutations near the tip of the V3 loop. Moreover, IC9564 could compete with the binding of V3 monoclonal antibodies 447-52D and 39F. IC9564 also competed with the binding of gp120/CD4 complexes to chemokine receptors. In summary, these results suggest that BA entry inhibitors can potently inhibit a broad spectrum of primary HIV-1 isolates by targeting the V3 loop of gp120.

Authors
Lai, W; Huang, L; Ho, P; Li, Z; Montefiori, D; Chen, C-H
MLA Citation
Lai, W, Huang, L, Ho, P, Li, Z, Montefiori, D, and Chen, C-H. "Betulinic acid derivatives that target gp120 and inhibit multiple genetic subtypes of human immunodeficiency virus type 1." Antimicrob Agents Chemother 52.1 (January 2008): 128-136.
PMID
17954689
Source
pubmed
Published In
Antimicrobial agents and chemotherapy
Volume
52
Issue
1
Publish Date
2008
Start Page
128
End Page
136
DOI
10.1128/AAC.00737-07

Activation and inhibition of the proteasome by betulinic acid and its derivatives.

This study discovered that betulinic acid (BA) is a potent proteasome activator that preferentially activates the chymotrypsin-like activity of the proteasome. Chemical modifications can transform BA into proteasome inhibitors. Chemical modifications at the C-3 position of BA resulted in compounds, such as dimethylsuccinyl BA (DSB), with various inhibitory activities against the human 20S proteasome. Interestingly, the proteasomal activation by BA and the inhibitory activity of DSB could be abrogated by introducing a side chain at the C-28 position. In summary, this study discovered a class of small molecules that can either activate or inhibit human proteasome activity depending on side chain modifications.

Authors
Huang, L; Ho, P; Chen, C-H
MLA Citation
Huang, L, Ho, P, and Chen, C-H. "Activation and inhibition of the proteasome by betulinic acid and its derivatives." FEBS Lett 581.25 (October 16, 2007): 4955-4959.
PMID
17904555
Source
pubmed
Published In
FEBS Letters
Volume
581
Issue
25
Publish Date
2007
Start Page
4955
End Page
4959
DOI
10.1016/j.febslet.2007.09.031

Induction of a nonproductive conformational change in gp120 by a small molecule HIV type 1 entry inhibitor.

Conformational changes in HIV-1 envelope glycoproteins, gp120 and gp41, is a dynamic process essential for HIV-1 entry. Here we show that a small molecule HIV-1 entry inhibitor, IC9564, induces a conformational change in gp120. The conformational change in gp120 is evidenced by a significant increase in the binding of a conformational monoclonal antibody 17b. As a result of the conformational effect, IC9564 significantly enhances the neutralizing activity of 17b. Unlike CD4, IC9564 does not trigger conformational changes in gp41. In fact, IC9564 inhibits CD4-induced conformational changes in gp41. Thus, IC9564 exploits the dynamic nature of gp120 by inducing a nonproductive gp120 conformation that is not able to trigger a conformational change in gp41 for membrane fusion.

Authors
Huang, L; Lai, W; Ho, P; Chen, CH
MLA Citation
Huang, L, Lai, W, Ho, P, and Chen, CH. "Induction of a nonproductive conformational change in gp120 by a small molecule HIV type 1 entry inhibitor." AIDS Res Hum Retroviruses 23.1 (January 2007): 28-32.
PMID
17263629
Source
pubmed
Published In
AIDS Research and Human Retroviruses
Volume
23
Issue
1
Publish Date
2007
Start Page
28
End Page
32
DOI
10.1089/aid.2006.0137

Synthesis and anti-HIV activity of Bif-functional triterpene derivatives

We previously reported a bi-functional betulinic acid derivative, A12-2 (4), containing an optimized C-28 side chain that exhibits potent anti-HIV activity by inhibiting both HIV-1 entry and maturation. Compound 4 contains C-3 and C-28 side chains that are pharmacophores for anti-HIV maturation and entry activity, respectively. The betulinic acid core, which serves as a molecular scaffold for compound 4, is also important for anti-HIV activity. The main purposes of the present study were to investigate the structure-activity relationships (SAR) of both the C-3 side chain and scaffold of 4. Further modification of the C-3 side chain of 4 suggested that both bulkier and smaller C-3 substituents negatively impacted the anti-HIV-1 activity. SAR study of the scaffold indicated that the betulinic acid moiety of 4 could be replaced with other scaffolds while still remaining active against HIV-1 replication. Among the synthesized compounds, the most effective molecular scaffold for anti-HIV activity remained to be betulinic acid (0.0026 μM), followed by moronic acid, ursolic acid, and oleanolic acid. On the other hand, substitution of the betulinic acid moiety of 4 with glycyrrhetinic acid or lithocholic acid completely abolished anti-HIV activity. Mechanism of action studies indicated that all active terpenoid analogs of 4 retained both anti-HIV-1 entry and anti-HIV-1 maturation activities. © 2007 Bentham Science Publishers Ltd.

Authors
Huang, L; Yu, D; Ho, P; Lee, K-H; Chen, C-H
MLA Citation
Huang, L, Yu, D, Ho, P, Lee, K-H, and Chen, C-H. "Synthesis and anti-HIV activity of Bif-functional triterpene derivatives." Letters in Drug Design and Discovery 4.7 (2007): 471-478.
Source
scival
Published In
Letters in drug design & discovery
Volume
4
Issue
7
Publish Date
2007
Start Page
471
End Page
478
DOI
10.2174/157018007781788561

Synthesis and anti-HIV activity of bi-functional betulinic acid derivatives.

Betulinic acid (BA) derivatives with a side chain at C-3 can inhibit HIV-1 maturation. On the other hand, BA derivatives with a side chain at C-28 can block HIV-1 entry. In order to combine the anti-maturation and anti-entry activities in a single molecule, new bi-functional BA derivatives containing side chains at C-3 and C-28 have been synthesized. The most potent compound ([[N-[3beta-O-(3',3'-dimethylsuccinyl)-lup-20(29)-en-28-oyl]-7-aminoheptyl]-carbamoyl]methane) inhibited HIV-1 at an EC50 of 0.0026 microM and was at least 20 times more potent than either the anti-maturation lead compound DSB or the anti-entry lead compound IC9564. This bi-functional BA derivative was active against both HIV entry and maturation. These results suggest that bi-functional BA derivatives with dual mechanisms of action have the potential to become clinically useful for AIDS therapy.

Authors
Huang, L; Ho, P; Lee, K-H; Chen, C-H
MLA Citation
Huang, L, Ho, P, Lee, K-H, and Chen, C-H. "Synthesis and anti-HIV activity of bi-functional betulinic acid derivatives." Bioorg Med Chem 14.7 (April 1, 2006): 2279-2289.
PMID
16314103
Source
pubmed
Published In
Bioorganic & Medicinal Chemistry
Volume
14
Issue
7
Publish Date
2006
Start Page
2279
End Page
2289
DOI
10.1016/j.bmc.2005.11.016

Moronic acid derivatives as novel potent anti-HIV agents

Authors
Sakurai, Y; Yu, D; Chen, C-H; Chang, F-R; Lee, K-H
MLA Citation
Sakurai, Y, Yu, D, Chen, C-H, Chang, F-R, and Lee, K-H. "Moronic acid derivatives as novel potent anti-HIV agents." March 26, 2006.
Source
wos-lite
Published In
ACS National Meeting Book of Abstracts
Volume
231
Publish Date
2006

Human immunodeficiency virus type 1 resistance to the small molecule maturation inhibitor 3-O-(3′,3′-dimethylsuccinyl)-betulinic acid is conferred by a variety of single amino acid substitutions at the CA-SP1 cleavage site in Gag

The compound 3-O-(3′,3′-dimethylsuccinyl)-betulinic acid (DSB) potently and specifically inhibits human immunodeficiency virus type 1 (HIV-) replication by delaying the cleavage of the CA-SP1 junction in Gag, leading to impaired maturation of the viral core. In this study, we investigated HIV-1 resistance to DSB by analyzing HIV-1 mutants encoding a variety of individual amino acid substitutions in the CA-SP1 cleavage site. Three of the substitutions were lethal to HIV-1 replication owing to a deleterious effect on particle assembly. The remaining mutants exhibited a range of replication efficiencies; however, each mutant was capable of replicating in the presence of concentrations of DSB that effectively inhibited wild-type HIV-1. Mutations conferring resistance to DSB also led to impaired binding of the compound to immature HIV-1 virions and loss of DSB-mediated inhibition of cleavage of Gag. Surprisingly, two of the DSB-resistant mutants retained an intermediate ability to bind the compound, suggesting that binding of DSB to immature HIV-1 particles may not be sufficient for antiviral activity. Overall, our results indicate that Gag amino acids L363 and A364 are critical for inhibition of HIV-1 replication by DSB and suggest that these residues form key contacts with the drug in the context of the assembling HIV-1 particle. These results have implications for the design of and screening for novel inhibitors of HIV-1 maturation. Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Authors
Zhou, J; Chin, HC; Aiken, C
MLA Citation
Zhou, J, Chin, HC, and Aiken, C. "Human immunodeficiency virus type 1 resistance to the small molecule maturation inhibitor 3-O-(3′,3′-dimethylsuccinyl)-betulinic acid is conferred by a variety of single amino acid substitutions at the CA-SP1 cleavage site in Gag." Journal of Virology 80.24 (2006): 12095-12101.
PMID
17035324
Source
scival
Published In
Journal of virology
Volume
80
Issue
24
Publish Date
2006
Start Page
12095
End Page
12101
DOI
10.1128/JVI.01626-06

Anti-AIDS agents 69. Moronic acid and other triterpene derivatives as novel potent anti-HIV agents

In a continuing structure-activity relationship study of potent anti-HIV agents, seven new triterpene derivatives were designed, synthesized, and evaluated for in vitro antiviral activity. Among them, moronic acid derivatives 19, 20, and 21 showed significant activity in HIV-1 infected H9 lymphocytes. Compounds 19 and 20 were also evaluated against HIV-1 NL4-3 and drug resistant strains in the MT-4 cell line. Compounds 19 and 20 showed better antiviral profiles than the betulinic acid analogue 8 (PA-457), which has successfully completed a Phase IIa clinical trial. Compound 20 showed potent anti-HIV activity with EC50 values of 0.0085 μM against NL4-3, 0.021 μM against PI-R (a multiple protease inhibitor resistant strain), and 0.13 μM against FHR-2 (an HIV strain resistant to 8). Promising compound 20 has become a new lead for modification, and further development of 20-related compounds as clinical trial candidates is warranted. © 2006 American Chemical Society.

Authors
Yu, D; Sakurai, Y; Chen, C-H; Chang, F-R; Huang, L; Kashiwada, Y; Lee, K-H
MLA Citation
Yu, D, Sakurai, Y, Chen, C-H, Chang, F-R, Huang, L, Kashiwada, Y, and Lee, K-H. "Anti-AIDS agents 69. Moronic acid and other triterpene derivatives as novel potent anti-HIV agents." Journal of Medicinal Chemistry 49.18 (2006): 5462-5469.
PMID
16942019
Source
scival
Published In
Journal of Medicinal Chemistry
Volume
49
Issue
18
Publish Date
2006
Start Page
5462
End Page
5469
DOI
10.1021/jm0601912

Inhibition of human immunodeficiency virus type 1 entry by a binding domain of Porphyromonas gingivalis gingipain

Human immunodeficiency virus (HIV) transmission through saliva is extremely low. Several oral components, including secretory immunoglobulin A and secretory leukocyte protease inhibitor, are known as potential inhibitory agents of HIV oral transmission. Here we examined anti-HIV activity of oral bacterial components. We showed that recombinant protein HGP44 derived from Porphyromonas gingivalis, one of the primary infectious agents of periodontitis, was capable of inhibiting HIV type 1 (HIV-1) replication. HGP44 bound specifically to HIV-1 gp120 and blocked HIV-1 envelope-mediated membrane fusion. These findings suggest that HGP44 of P. gingivalis can inhibit HIV-1 infection by blocking HIV-1 entry. Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Authors
Xie, H; Belogortseva, NI; Wu, J; Lai, W-H; Chen, C-H
MLA Citation
Xie, H, Belogortseva, NI, Wu, J, Lai, W-H, and Chen, C-H. "Inhibition of human immunodeficiency virus type 1 entry by a binding domain of Porphyromonas gingivalis gingipain." Antimicrobial Agents and Chemotherapy 50.9 (2006): 3070-3074.
PMID
16940103
Source
scival
Published In
Antimicrobial agents and chemotherapy
Volume
50
Issue
9
Publish Date
2006
Start Page
3070
End Page
3074
DOI
10.1128/AAC.01578-05

Mechanism of action and resistant profile of anti-HIV-1 coumarin derivatives.

Dicamphanoyl khellactone (DCK) is a coumarin derivative that can potently inhibit HIV-1 replication. DCK does not inhibit RNA-dependent DNA synthesis. However, an HIV reverse transcriptase (RT) inhibitor-resistant strain, HIV-1/RTMDR1, is resistant to DCK. Thus, it is possible that HIV-1 RT is the target of DCK. To test this possibility, DCK-resistant viruses were selected in the presence of DCK. Our results indicate that a single amino acid mutation, E138K in HIV-1 RT, is sufficient to confer DCK resistance. Interestingly, a DCK derivative, 3'R,4'R-Di-O-(-)-camphanoyl-2-ethyl-2',2'-dimethyldihydropyrano[2,3-f]chromone (DCP8), is effective against HIV-1/RTMDR1. However, the DCK-escape virus carrying the E138K mutation remains resistant to DCP8. Since DCK did not inhibit the RNA-dependent DNA polymerase activity of HIV-1 RT when using poly-rA or poly-rC as template, we evaluated the effect of DCK on the DNA-dependent DNA polymerase activity of HIV-1 RT. Our results indicate that DCK can inhibit the DNA-dependent DNA polymerase activity of HIV-1 RT. In conclusion, DCK is a unique HIV-1 RT inhibitor that inhibits the DNA-dependent DNA polymerase activity. In contrast, DCK did not significantly affect the RNA-dependent DNA polymerase activity when poly-rA or poly-rC was used as templates. An E138K mutation in the non-nucleoside RT inhibitors (NNRTIs) binding pocket of HIV-1 RT confers resistance to DCK and its chromone derivative, DCP8.

Authors
Huang, L; Yuan, X; Yu, D; Lee, KH; Chen, CH
MLA Citation
Huang, L, Yuan, X, Yu, D, Lee, KH, and Chen, CH. "Mechanism of action and resistant profile of anti-HIV-1 coumarin derivatives." Virology 332.2 (February 20, 2005): 623-628.
PMID
15680427
Source
pubmed
Published In
Virology
Volume
332
Issue
2
Publish Date
2005
Start Page
623
End Page
628
DOI
10.1016/j.virol.2004.11.033

The molecular targets of anti-HIV-1 triterpenes, an update

Pentacyclic triterpenes have been found in many plants and can be isolated from any parts of the plant. Triterpene derivatives were shown to have biological activities including anti-HIV-1 and anti-cancer. The modes of action of the anti-HIV-1 triterpenes have been reported to be associated with virus entry, reverse transcription, virus assembly, and maturation. This review will focus on the mechanisms of action of anti-HIV triterpenes and the structural features that contribute to their anti-HIV-1 activity. Two classes of triterpenes are particularly potent and highly selective: one inhibits HIV-1 entry and the other interferes with HIV-1 maturation. Significant progresses have been made in identifying the mechanisms of action for these two classes of anti-HIV-1 triterpenes. The anti-HIV-1 entry activity is associated with a side chain at position 28 and the anti-HIV-1 maturation activity is associated with the pharmacophore at position 3. Compounds containing both of the pharmacophores at 3 and 28 positions can potently inhibit HIV-1 through their anti-HIV-1 entry and maturation activities. Although the detail mechanisms of action remains unclear, the anti-entry triterpenes target HIV-1 envelope glycoprotein, and the anti-maturation triterpenes affect the processing of the HIV-1 gag protein, CA-SP1. © 2005 Bentham Science Publishers Ltd.

Authors
Huang, L; Chen, CH
MLA Citation
Huang, L, and Chen, CH. "The molecular targets of anti-HIV-1 triterpenes, an update." Medicinal Chemistry Reviews - Online 2.5 (2005): 423-427.
Source
scival
Published In
Vascular disease prevention
Volume
2
Issue
5
Publish Date
2005
Start Page
423
End Page
427

Inhibition of HIV-1 maturation via drug association with the viral Gag protein in immature HIV-1 particles

The small molecule 3-O-(3′,3′-dimethylsuccinyl)-betulinic acid (DSB) potently inhibits human immunodeficiency virus, type 1 (HIV-1) replication by interfering with proteolytic cleavage of the viral Gag protein at a specific site. Here we have demonstrated that the antiviral mechanism involves the association of DSB with Gag at a 1:1 stoichiometry within immature HIV-1 particles. The binding was specific, as mutations in Gag that confer resistance to DSB inhibited the association, which could be competed by DSB but not by the inactive compound betulinic acid. The addition of DSB to purified immature viral cores inhibited the cleavage of Gag at the CA-SP1 junction in vitro, thus reproducing the effect of the drug when present during maturation of HIV-1 particles. Based on these findings, we propose a model in which a trimer of DSB associates with the CA-SP1 junction of adjacent subunits within the Gag polymer. The model may explain the ability of highly similar compounds to specifically target the seemingly unrelated steps of HIV-1 maturation and virus entry. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.

Authors
Zhou, J; Huang, L; Hachey, DL; Chen, CH; Aiken, C
MLA Citation
Zhou, J, Huang, L, Hachey, DL, Chen, CH, and Aiken, C. "Inhibition of HIV-1 maturation via drug association with the viral Gag protein in immature HIV-1 particles." Journal of Biological Chemistry 280.51 (2005): 42149-42155.
PMID
16251182
Source
scival
Published In
The Journal of biological chemistry
Volume
280
Issue
51
Publish Date
2005
Start Page
42149
End Page
42155
DOI
10.1074/jbc.M508951200

The discovery of a class of novel HIV-1 maturation inhibitors and their potential in the therapy of HIV

Although HIV infection is now primarily treated with reverse transcriptase and protease inhibitors, HIV therapy must look toward new drugs with novel mechanism(s) of action to both improve efficacy and address the growing problem of drug resistance. Using natural products as a source of biologically active compounds, our drug discovery program has successfully optimised the natural product betulinic acid to the first-in-class maturation inhibitor 3-O-(3′,3′-dimethylsuccinyl)-betulinic acid (DSB). DSB's unique viral target has been identified as a late step in Gag processing. Specifically, it inhibits the cleavage of the capsid precursor, CA-SP1, resulting in a block to the processing of mature capsid protein leading to a defect in viral core condensation. DSB represents a unique class of anti-HIV compounds that inhibit virus maturation and provide additional opportunities for anti-HIV therapy. In this review, the discovery of DSB and its mode of action are summarised. Anti-AIDS Agents part 64. For part 63 in the series, see YU D, LEE KH: Recent progress and prospects on plant-derived anti-HIV agents and analogs. In: Medicinal Chemistry of Bioactive Natural Products. XT Liang, WS Fang (Eds), Wiley, New York, USA (2005) (in Press). © 2005 Ashley Publications Ltd.

Authors
Yu, D; Wild, CT; Martin, DE; Morris-Natschke, SL; Chen, C-H; Allaway, GP; Lee, K-H
MLA Citation
Yu, D, Wild, CT, Martin, DE, Morris-Natschke, SL, Chen, C-H, Allaway, GP, and Lee, K-H. "The discovery of a class of novel HIV-1 maturation inhibitors and their potential in the therapy of HIV." Expert Opinion on Investigational Drugs 14.6 (2005): 681-693.
PMID
16004596
Source
scival
Published In
Expert Opinion on Investigational Drugs
Volume
14
Issue
6
Publish Date
2005
Start Page
681
End Page
693
DOI
10.1517/13543784.14.6.681

Betulinic acid derivatives as HIV-1 antivirals

Betulinic acid (BA) derivatives are low molecular weight organic compounds synthesized from a plant-derived natural product. Several BA derivatives are potent and highly selective inhibitors of HIV-1. Depending on the specific side-chain modification, these compounds function by inhibiting HIV fusion or, as recently demonstrated, by interfering with a specific step in HIV-1 maturation. BA derivatives have potential as novel HIV-1 therapies, and additional studies of their mechanisms of action are likely to further define the novel targets of these compounds and elucidate the basic biology of HIV-1 fusion and maturation. In this review, recent studies of the novel mechanisms of action of this interesting class of antiviral compounds are discussed.

Authors
Aiken, C; Chen, CH
MLA Citation
Aiken, C, and Chen, CH. "Betulinic acid derivatives as HIV-1 antivirals." Trends in Molecular Medicine 11.1 (2005): 31-36.
PMID
15649820
Source
scival
Published In
Trends in Molecular Medicine
Volume
11
Issue
1
Publish Date
2005
Start Page
31
End Page
36
DOI
10.1016/j.molmed.2004.11.001

Inhibition of HIV-1 entry by inducing a nonproductive conformational change in gp120

Authors
Lai, W; Huang, L; Ho, P; Yuan, X; Chen, C-H
MLA Citation
Lai, W, Huang, L, Ho, P, Yuan, X, and Chen, C-H. "Inhibition of HIV-1 entry by inducing a nonproductive conformational change in gp120." 2005.
Source
wos-lite
Published In
Retrovirology
Volume
2
Publish Date
2005
DOI
10.1186/1742-4690-2-S1-P54

Conformation of gp120 determines the sensitivity of HIV-1 DH012 to the entry inhibitor IC9564.

The HIV-1 envelope glycoprotein gp120 is the key determinant for the anti-HIV-1 entry activity of IC9564. A T198P mutation in the gp120 of the HIV-1 primary isolate, DH012, drastically increases IC9564 sensitivity, which can be reversed by growing the virus in the presence of IC9564. The reversed resistant variants contain a P198S mutation that fully confers the drug-resistant phenotype. Although the amino acid residue at position 198 of gp120 can alter IC9564 sensitivity, results from this study suggest that T198 is not the direct target of the compound. The mutation at position 198 appears to affect the conformation of gp120 and subsequently decreases the accessibility of the drug target. This conformational effect is evidenced by the fact that the T198P mutation significantly increases the neutralizing activity of the conformational antibodies, 1b12 and 48d. On the other hand, the IC9564 escape variant with the P198S mutation is resistant to these conformational antibodies and highly sensitive to the potent neutralizing antiserum, C1206, which recognizes a conformational epitope involving the sequences from V1, V2, and V3 regions in gp120. Thus, results from this study indicate that the conformation of gp120 can be exploited by HIV-1 to escape IC9564.

Authors
Yuan, X; Huang, L; Ho, P; Labranche, C; Chen, CH
MLA Citation
Yuan, X, Huang, L, Ho, P, Labranche, C, and Chen, CH. "Conformation of gp120 determines the sensitivity of HIV-1 DH012 to the entry inhibitor IC9564." Virology 324.2 (July 1, 2004): 525-530.
PMID
15207637
Source
pubmed
Published In
Virology
Volume
324
Issue
2
Publish Date
2004
Start Page
525
End Page
530
DOI
10.1016/j.virol.2004.04.009

Substituted-3 ' R,4 ' R-dl-(O)-(-)-camphanoyl-2 ',2 '- dimethyldihydropyrano[2,3-F]chromone (DCP) derivatives as potent anti-HIV agents.

Authors
Yu, DL; Chen, CH; Brossi, A; Kilgore, N; Lee, KH
MLA Citation
Yu, DL, Chen, CH, Brossi, A, Kilgore, N, and Lee, KH. "Substituted-3 ' R,4 ' R-dl-(O)-(-)-camphanoyl-2 ',2 '- dimethyldihydropyrano[2,3-F]chromone (DCP) derivatives as potent anti-HIV agents." March 28, 2004.
Source
wos-lite
Published In
ACS National Meeting Book of Abstracts
Volume
227
Publish Date
2004
Start Page
U8
End Page
U8

Bifunctional anti-human immunodeficiency virus type 1 small molecules with two novel mechanisms of action.

A class of betulinic acid derivatives was synthesized to target two critical steps in the human immunodeficiency virus type 1 (HIV-1) replication cycle, entry and maturation. Each mechanism of HIV-1 inhibition is distinct from clinically available anti-HIV therapeutics. The viral determinants of the antientry and antimaturation activities are the bridging sheet of HIV-1 gp120 and the P24/p2 cleavage site, respectively.

Authors
Huang, L; Yuan, X; Aiken, C; Chen, CH
MLA Citation
Huang, L, Yuan, X, Aiken, C, and Chen, CH. "Bifunctional anti-human immunodeficiency virus type 1 small molecules with two novel mechanisms of action." Antimicrob Agents Chemother 48.2 (February 2004): 663-665.
PMID
14742233
Source
pubmed
Published In
Antimicrobial agents and chemotherapy
Volume
48
Issue
2
Publish Date
2004
Start Page
663
End Page
665

Anti-AIDS agents. 60. Substituted 3′R,4′R-di-O-(-)-camphanoyl- 2′,2′-dimethyldihydropyrano[2,3-f]chromone (DCP) analogues as potent anti-HIV agents

Synthesis of positional isomers is a commonly used technique in drug design. Accordingly, based on prior SAR studies of 3′R,4′R-di-O-(S)- camphanoyl-(+)-cis-khellactone (DCK, 1) analogues, a series of mono- and disubstituted chromone derivatives of 3′R,4′R-di-O-(-)camphanoyl- 2′,2′-dimethyldihydropyrano[2,3-f]chromone (DCP, 4) were designed and synthesized. Together with 1 and 4-methyl DCK (2), all newly synthesized DCP analogues (4-21) were screened for anti-HIV-1 activity against a non-drug-resistant strain in H9 lymphocytes and a multiple reverse transcriptase (RT) inhibitor-resistant strain in the MT4 cell line. Several DCP analogues (4, 5, 7, 8, 13, and 17) exhibited extremely high anti-HIV activity in the nondrug-resistant strain assay, with EC50 values ranging from 0.00032 to 0.0057 μM and remarkable therapeutic indexes (TI) ranging from 5.6 × 103 to 1.16 × 105, which were similar to those of 2 (EC50 0.0059 μM, TI > 6.6 × 103) and better than those of 1 (EC50 0.049 μM, TI > 328). Even more promisingly, some DCP analogues also showed activity against a multi-RT inhibitor-resistant strain, HIV-1 RTMDR1, whereas most DCK analogues did not. The most significant compound was 8, with an EC50 value of 0.06 μM and TI of 718 against the multi-RT inhibitor-resistant HIV-1 strain. Compounds 9 and 10 also showed good activity with an EC50 value of 0.14 μM, and TIs of 272 and >111, respectively. 2-Ethyl DCP (8) exhibited the best anti-HIV activity in both assays. Further development of 8-related compounds as clinical trial candidates is warranted.

Authors
Yu, D; Chen, C-H; Brossi, A; Lee, K-H
MLA Citation
Yu, D, Chen, C-H, Brossi, A, and Lee, K-H. "Anti-AIDS agents. 60. Substituted 3′R,4′R-di-O-(-)-camphanoyl- 2′,2′-dimethyldihydropyrano[2,3-f]chromone (DCP) analogues as potent anti-HIV agents." Journal of Medicinal Chemistry 47.16 (2004): 4072-4082.
PMID
15267246
Source
scival
Published In
Journal of Medicinal Chemistry
Volume
47
Issue
16
Publish Date
2004
Start Page
4072
End Page
4082
DOI
10.1021/jm0400505

The sequence of the CA-SP1 junction accounts for the differential sensitivity of HIV-1 and SIV to the small molecule maturation inhibitor 3-O-{3′, 3′-dimethylsuccinyl}-betulinic acid

Background. Despite the effectiveness of currently available antiretroviral therapies in the treatment of HIV-1 infection, a continuing need exists for novel compounds that can be used in combination with existing drugs to slow the emergence of drug-resistant viruses. We previously reported that the small molecule 3-O-{3′,3′-dimethylsuccinyl}-betulinic acid (DSB) specifically inhibits HIV-1 replication by delaying the processing of the CA-SP1 junction in Pr55Gag. By contrast, SIVmac239 replicates efficiently in the presence of high concentrations of DSB. To determine whether sequence differences in the CA-SP1 junction can fully account for the differential sensitivity of HIV-1 and SIV to DSB, we engineered mutations in this region of two viruses and tested their sensitivity to DSB in replication assays using activated human primary CD4+ T cells. Results. Substitution of the P2 and P1 residues of HIV-1 by the corresponding amino acids of SIV resulted in strong resistance to DSB, but the mutant virus replicated with reduced efficiency. Conversely, replication of an SIV mutant containing three amino acid substitutions in the CA-SP1 cleavage site was highly sensitive to DSB, and the mutations resulted in delayed cleavage of the CA-SP1 junction in the presence of the drug. Conclusions. These results demonstrate that the CA-SP1 junction in Pr55Gag represents the primary viral target of DSB. They further suggest that the therapeutic application of DSB will be accompanied by emergence of mutant viruses that are highly resistant to the drug but which exhibit reduced fitness relative to wild type HIV-1. © 2004 Zhou et al; licensee BioMed Central Ltd.

Authors
Zhou, J; Chen, CH; Aiken, C
MLA Citation
Zhou, J, Chen, CH, and Aiken, C. "The sequence of the CA-SP1 junction accounts for the differential sensitivity of HIV-1 and SIV to the small molecule maturation inhibitor 3-O-{3′, 3′-dimethylsuccinyl}-betulinic acid." Retrovirology 1 (2004).
PMID
15225375
Source
scival
Published In
Retrovirology
Volume
1
Publish Date
2004
DOI
10.1186/1742-4690-1-15

Small-Molecule Inhibition of Human Immunodeficiency Virus Type 1 Replication by Specific Targeting of the Final Step of Virion Maturation

Despite the effectiveness of currently available human immunodeficiency virus type 1 (HIV-1) therapies, a continuing need exists for new drugs to treat HIV-1 infection. We investigated the mechanism by which 3-O-{3′,3′ -dimethylsuccinyl}betulinic acid (DSB) inhibits HIV-1 replication. DSB functions at a late stage of the virus life cycle but does not inhibit the HIV-1 protease in vitro or interfere with virus assembly or release. DSB specifically delays the cleavage of Gag between the capsid (CA) and p2, resulting in delayed formation of the mature viral core and reduced HIV-1 infectivity. Replication of simian immunodeficiency virus (SIV) was resistant to DSB; however, a chimeric SIV carrying CA-p2 sequences from HIV-1 was inhibited by the drug, indicating that susceptibility to DSB maps to the CA-p2 region of the HIV-1 Gag protein. A single point mutation at the CA-p2 cleavage site of HIV-1 conferred strong resistance to DSB, confirming the target of the drug. HIV-1 strains that are resistant to a variety of protease inhibitors were sensitive to DSB. These findings indicate that DSB specifically protects the CA-p2 cleavage site from processing by the viral protease during virion maturation, thereby revealing a novel mechanism for pharmacologic inhibition of HIV-1 replication.

Authors
Zhou, J; Yuan, X; Dismuke, D; Forshey, BM; Lundquist, C; Lee, K-H; Aiken, C; Chen, CH
MLA Citation
Zhou, J, Yuan, X, Dismuke, D, Forshey, BM, Lundquist, C, Lee, K-H, Aiken, C, and Chen, CH. "Small-Molecule Inhibition of Human Immunodeficiency Virus Type 1 Replication by Specific Targeting of the Final Step of Virion Maturation." Journal of Virology 78.2 (2004): 922-929.
PMID
14694123
Source
scival
Published In
Journal of Virology
Volume
78
Issue
2
Publish Date
2004
Start Page
922
End Page
929
DOI
10.1128/JVI.78.2.922-929.2004

Potential drug targets on the HIV-1 envelope glycoproteins, gp120 and gp41

HIV-1 entry is an attractive target for anti-HIV-1 therapy. However, there are no entry inhibitors approved for the clinical treatment of HIV 1 Infection. This is likely to be changed in the near future since promising HIV-1 entry inhibitors, such as T20 and some chemokine receptor antagonists, are in the pipeline to join the repertoire of anti-HIV-1 therapeutics. This review will focus on what might be potential targets on the key components of the viral entry machinery, gp120 and gp41. These two molecules are the viral proteins responsible for HIV-1 entry. Binding to CD4 induces a series of structural changes in gp120 and allows it to interact with chemokine receptors. The receptor binding eventually triggers conformational changes in gp41, which result in the formation of a fusion active molecule to attack the cell membrane. The structural and functional motifs that operate this delicate fusion machinery could become the Achilles' heel of the virus.

Authors
Huang, L; Zhang, L; Chen, CH
MLA Citation
Huang, L, Zhang, L, and Chen, CH. "Potential drug targets on the HIV-1 envelope glycoproteins, gp120 and gp41." Current Pharmaceutical Design 9.18 (2003): 1453-1462.
PMID
12769725
Source
scival
Published In
Current Pharmaceutical Design
Volume
9
Issue
18
Publish Date
2003
Start Page
1453
End Page
1462
DOI
10.2174/1381612033454720

Neutralization epitopes of the HIV-1 primary isolate DH012

To study HIV-1 primary isolate neutralization, we have used DH012 as a model to study the immunogenicity of several DH012 immunogens and determine the potential neutralization epitopes in the virus envelope glycoprotein. Previously, we identified that DH012 infected animals mount potent neutralizing activity against a conformational epitope (CEV) that involves multiple variable regions. In this study, we show that the conformational epitope can be reconstituted with one gp120 recombinant fragment containing sequences from the V1/V2 loop and the bridging sheet of gp120 and a V3 peptide. In contrast to DH012 infection, we previously demonstrated that animals immunized with DH012 gp120 induced potent neutralizing antibodies directed at the V3 domain of gp120. In this study, a second neutralizing activity against the V1/V2 region of gp120 was identified from the same guinea pig sera. In summary, several neutralization epitopes are identified on DH012, including the CEV, V1/V2, V3, 17b, IgG1b12, and 2G12 epitopes. Infectious DH012 virus carrying oligomeric envelope appears to raise primarily neutralizing antibodies that recognize a discontinuous conformationally dependent epitope whereas the monomeric gp120 induces antibodies that are primarily directed at epitopes in the V3 and V1/V2 domains. The DH012 neutralizing epitopes, such as V1/V2 and V3, are either cryptic or poorly immunogenic in chimpanzees. However, immunogens, such as gp120, could be designed to induce neutralizing activity against epitopes that are poorly immunogenic, such as V1/V2 of DH012, in the native envelope glycoproteins. © 2003 Elsevier Science Ltd. All rights reserved.

Authors
Zhu, C; Matthews, TJ; Chen, C-H
MLA Citation
Zhu, C, Matthews, TJ, and Chen, C-H. "Neutralization epitopes of the HIV-1 primary isolate DH012." Vaccine 21.23 (2003): 3301-3306.
PMID
12804861
Source
scival
Published In
Vaccine
Volume
21
Issue
23
Publish Date
2003
Start Page
3301
End Page
3306
DOI
10.1016/S0264-410X(03)00218-4

Anti-AIDS agents 49. Synthesis, anti-HIV, and anti-fusion activities of IC9564 analogues based on betulinic acid

The betulinic acid derivative IC9564 inhibits human immunodeficiency virus (HIV)-1 entry. Among a series of IC9564 derivatives, 5 and 20 were the most promising compounds against HIV infection with EC50 values of 0.33 and 0.46 μM, respectively. Both compounds inhibited syncytium formation with EC50 values of 0.40 and 0.33 μM, respectively. The comparable EC50 values in the two assays suggested that these compounds are fusion inhibitors. The structure-activity relationship data also indicated that a double bond in IC9564 can be eliminated and the statine moiety can be replaced with L-leucine while retaining anti-HIV activity.

Authors
Sun, I-C; Chen, C-H; Kashiwada, Y; Wu, J-H; Wang, H-K; Lee, K-H
MLA Citation
Sun, I-C, Chen, C-H, Kashiwada, Y, Wu, J-H, Wang, H-K, and Lee, K-H. "Anti-AIDS agents 49. Synthesis, anti-HIV, and anti-fusion activities of IC9564 analogues based on betulinic acid." Journal of Medicinal Chemistry 45.19 (2002): 4271-4275.
PMID
12213068
Source
scival
Published In
Journal of Medicinal Chemistry
Volume
45
Issue
19
Publish Date
2002
Start Page
4271
End Page
4275
DOI
10.1021/jm020069c

Molecular targets of anti-HIV-1 triterpenes

Pentacyclic triterpenes have been found in many plants and may be isolated from any part of the plant. Triterpene derivatives were shown to have biological activities including anti-HIV-1 and anti-cancer activities. The modes of action of the anti-HIV-1 triterpenes have been reported to be associated with the virus entry, reverse transcription, virus assembly and maturation. This review will focus on the mechanisms of action of anti-HIV triterpenes and the structural features that contribute to their anti-HIV-1 activity and site of action.

Authors
Huang, L; Chen, CH
MLA Citation
Huang, L, and Chen, CH. "Molecular targets of anti-HIV-1 triterpenes." Current Drug Targets - Infectious Disorders 2.1 (2002): 33-36.
PMID
12462151
Source
scival
Published In
Current Drug Targets - Infectious Disorders
Volume
2
Issue
1
Publish Date
2002
Start Page
33
End Page
36

Role of human immunodeficiency virus (HIV) type 1 envelope in the anti-HIV activity of the betulinic acid derivative IC9564

Authors
Holz-Smith, SL; Sun, IC; Jin, L; Matthews, TJ; Lee, KH; Chen, CH
MLA Citation
Holz-Smith, SL, Sun, IC, Jin, L, Matthews, TJ, Lee, KH, and Chen, CH. "Role of human immunodeficiency virus (HIV) type 1 envelope in the anti-HIV activity of the betulinic acid derivative IC9564." ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 45.1 (January 2001): 60-66.
PMID
11120945
Source
wos-lite
Published In
Antimicrobial agents and chemotherapy
Volume
45
Issue
1
Publish Date
2001
Start Page
60
End Page
66
DOI
10.1128/AAC.45.1.60-66.2001

The role of the third β strand in gp120 conformation and neutralization sensitivity of the HIV-1 primary isolate DH012

Neutralization of HIV-1 primary isolates has been a tremendous challenge for AIDS vaccine development. Here,we identify a single amino acid change (T198P) in gp120 that alters the neutralization sensitivity of the primary isolate DH012 to antibodies against multiple neutralization epitopes that include the V3, CD4-induced, and CD4 binding sites in gp120. This mutation is located in the V1/V2 stem region that forms the third β strand (β3) of the bridging sheet of gp120. The conformation of variable loops, especially V1/V2 and V3, was proposed to regulate the accessibility of these neutralization epitopes. The results of this study indicate a direct association between the V1/V2 and V3 loops of DH012 gp120. The single amino acid mutation T198P in the β3 severely compromises the interaction between the V1/V2 and V3 loops. These results suggest that interaction of V1/V2 and V3 can mask the neutralization epitopes and that the β3 plays a critical role in determining the neutralization sensitivity by modulating the interaction. This study provides an insight into why primary isolates are relatively resistant to antibody neutralization and might facilitate the development of anti-HIV strategies against HIV-1 infection.

Authors
Zhu, C-B; Zhu, L; Holz-Smith, S; Matthews, TJ; Chen, CH
MLA Citation
Zhu, C-B, Zhu, L, Holz-Smith, S, Matthews, TJ, and Chen, CH. "The role of the third β strand in gp120 conformation and neutralization sensitivity of the HIV-1 primary isolate DH012." Proceedings of the National Academy of Sciences of the United States of America 98.26 (2001): 15227-15232.
PMID
11734627
Source
scival
Published In
Proceedings of the National Academy of Sciences of USA
Volume
98
Issue
26
Publish Date
2001
Start Page
15227
End Page
15232
DOI
10.1073/pnas.261359098

Induction and characterization of neutralizing antibodies against a human immunodeficiency virus type 1 primary isolate

Chimpanzees infected with the primary isolate DH012 mount potent neutralizing antibodies. This DH012 neutralizing activity is highly strain specific. Immune sera from guinea pigs immunized with recombinant DH012 gp120 could also neutralize this primary isolate. The neutralizing activity in chimpanzee and guinea pig sera against wild-type DH012 appears to be independent of a linear epitope in the V3 region of gp120. Interestingly, the neutralization escape mutant derived from growing DH012 in the presence of the potent neutralizing chimpanzee serum is at least 50-fold more sensitive than wild-type DH012 to neutralization by guinea pig immune sera. The unusually potent neutralizing activity against the DH012 neutralization-resistant virus is due to the presence of anti-V3 antibodies in guinea pig sera. These results suggested that recombinant gp120 could induce neutralizing antibodies against primary isolate DH012. The V3 of wild-type DH012 is poorly immunogenic in infected chimpanzees and is not accessible to neutralizing V3 antibodies. It is likely that this cryptic V3 region became exposed when the virus escaped the neutralizing activity of the chimpanzee serum.

Authors
Chen, C-H; Jin, L; Zhu, C; Holz-Smith, S; Matthews, TJ
MLA Citation
Chen, C-H, Jin, L, Zhu, C, Holz-Smith, S, and Matthews, TJ. "Induction and characterization of neutralizing antibodies against a human immunodeficiency virus type 1 primary isolate." Journal of Virology 75.14 (2001): 6700-6704.
PMID
11413338
Source
scival
Published In
Journal of Virology
Volume
75
Issue
14
Publish Date
2001
Start Page
6700
End Page
6704
DOI
10.1128/JVI.75.14.6700-6704.2001

Monoclonal antibodies that bind to the core of fusion-active glycoprotein 41.

The heptad repeat regions HR1 and HR2 of HIV-1 gp41 can associate to form heterooligomers through helical coil-coil interactions that are believed to play a key role in virus-induced membrane fusion. The HR1/HR2 complex was proposed to be the core structure of the fusion-active conformation of gp41. Here, we show that two human monoclonal antibodies, Fab-d and 50-69, specifically recognize the putative fusion-active conformation of gp41. Fab-d binding requires the interaction between the HR1 and HR2 regions of gp41. The reactivity of human monoclonal antibody 50-69 to the C terminus of the HR1 sequence is dependent on the helical structure of HR1. It appears that HR2 is able to interact with HR1 and, subsequently, induce an epitope in HR1 that is required for 50-69 binding. Mutations that disrupt the helical structure of HR1 significantly compromise Fab-d and 50-69 binding. Although the epitopes are not identical, the ability of Fab-d to partially compete with 50-69 binding suggests a close proximity of the two epitopes. Antibodies that are able to interact with the core of the putative fusion-active gp41 may be useful in further unveiling the mechanism of HIV-induced membrane fusion.

Authors
Chen, CH; Greenberg, ML; Bolognesi, DP; Matthews, TJ
MLA Citation
Chen, CH, Greenberg, ML, Bolognesi, DP, and Matthews, TJ. "Monoclonal antibodies that bind to the core of fusion-active glycoprotein 41." AIDS Res Hum Retroviruses 16.18 (December 10, 2000): 2037-2041.
PMID
11153086
Source
pubmed
Published In
AIDS Research and Human Retroviruses
Volume
16
Issue
18
Publish Date
2000
Start Page
2037
End Page
2041
DOI
10.1089/088922200750054765

Identification of gp120 regions targeted by a highly potent neutralizing antiserum elicited in a chimpanzee inoculated with a primary human immunodeficiency virus type 1 isolate

Authors
Cho, MW; Lee, MK; Chen, CH; Matthews, T; Martin, MA
MLA Citation
Cho, MW, Lee, MK, Chen, CH, Matthews, T, and Martin, MA. "Identification of gp120 regions targeted by a highly potent neutralizing antiserum elicited in a chimpanzee inoculated with a primary human immunodeficiency virus type 1 isolate." JOURNAL OF VIROLOGY 74.20 (October 2000): 9749-9754.
PMID
11000249
Source
wos-lite
Published In
Journal of virology
Volume
74
Issue
20
Publish Date
2000
Start Page
9749
End Page
9754
DOI
10.1128/JVI.74.20.9749-9754.2000

Herpesvirus saimiri transformation of HIV type 1 suppressive CD8+ lymphocytes from an HIV type 1-infected asymptomatic individual.

CD8+ T lymphocytes from HIV+ individuals can potently suppress HIV-1 replication in a noncytolytic manner. This suppression appears to be multifactorial and the molecules contributing have not been fully elucidated. As an approach to this question we used herpesvirus saimiri (HVS) to transform CD8+ T lymphocytes from an HIV+ asymptomatic donor to a continuously growing, activation-independent, IL-2-dependent phenotype. The transformed cell population, termed CD8(HVS), had an activated phenotype, contained HVS sequences, did not shed infectious HVS virus, and was polyclonal. The CD8(HVS) cells, despite the absence of detectable CTL activity, potently suppressed HIV-1 production by both autologous and heterologous CD4+ cells from infected donors. The CD8(HVS) cells in coculture also suppressed virus production from PBMCs acutely infected with syncytium-inducing (SI) strains or NSI primary isolates of HIV-1. The supernatants from the CD8(HVS) cells and their concentrates derived from these supernatants were suppressive to NSI primary isolates of HIV-1 but not to SI strains. Fractionation of these concentrates showed that the suppressive activity was associated with low molecular mass (6500- to 19,300-Da) protein species. Western blotting and ELISA indicated that the CC chemokines MIP-1alpha, MIP-1beta, and RANTES were present in these fractions. Antibody-blocking studies with antibodies to the CC chemokines indicated that a significant portion of the soluble HIV-suppressive activity was due to these molecules. However, these experiments also suggested the inhibitory activity of the CD8(HVS) cells in coculture is not due exclusively to the CC chemokines. The HVS-transformed cells provide a useful tool for the study of noncytolytic CD8+ T lymphocyte-mediated suppression of HIV-1.

Authors
Lacey, SF; Weinhold, KJ; Chen, CH; McDanal, C; Oei, C; Greenberg, ML
MLA Citation
Lacey, SF, Weinhold, KJ, Chen, CH, McDanal, C, Oei, C, and Greenberg, ML. "Herpesvirus saimiri transformation of HIV type 1 suppressive CD8+ lymphocytes from an HIV type 1-infected asymptomatic individual." AIDS Res Hum Retroviruses 14.6 (April 10, 1998): 521-531.
PMID
9566555
Source
pubmed
Published In
AIDS Research and Human Retroviruses
Volume
14
Issue
6
Publish Date
1998
Start Page
521
End Page
531
DOI
10.1089/aid.1998.14.521

Anti-AIDS agents. 34. Synthesis and structure-activity relationships of betulin derivatives as anti-HIV agents

Succinyl and 3'-substituted glutaryl betulin derivatives showed stronger anti-HIV activity and higher therapeutic index (TI) values than their dihydrobetulin counterparts, with ratios of 1.2:1 to 15:1 (cf. 7 and 15, 9 and 17, 10 and 18, 11 and 19, and 12 and 20). For various 3'-substituted glutaryl compounds, the order of anti-HIV effects, from strong to weak inhibition, was 3',3'-dimethyl, 3'-methyl, 3'-ethyl-3'-methyl, followed by 3',3'-tetramethylene glutaryl derivatives (10 > 9 > 11 > 12, 18 > 17 > 19 > 20). The most potent compound, 10, has two 3',3'-dimethylglutaryl groups and displays significant anti-HIV potency with an EC50 value of 0.000 66 μM and a TI of 21 515. Results for compounds (22 and 23) without a C-3 acyl group confirmed the importance of the C-3 acyl group to the anti-HIV effect. With 3',3'-tetramethylene glutaryl derivatives, triacyl 29 showed stronger inhibition than diacyl 12; in contrast, 3',3'-dimethylglutaryl compounds displayed opposite results. 3-Keto compounds (35 and 36) and 2,3-dihydro compounds (39 and 40) had EC50 values in the range of 4.3-10.0 μM, suggesting that A ring modification led to decreased potency. The reduced activity of amide (33 and 34), ester (41), and oxime (42) analogues suggested that the orientation and linkage of the C-3 acyl side chain play crucial roles in the potent anti-HIV activity. Finally, replacing the C-28 acyl group with a bulky non-carboxylic group produced a less potent compound (44). In the study of mechanism of action, our results indicated that fusion is not the primary target for the anti-HIV activity of 10. It appears to inhibit HIV replication at a late stage of the viral life cycle, i.e., after viral protein synthesis.

Authors
Sun, I-C; Wang, H-K; Kashiwada, Y; Shen, J-K; Cosentino, LM; Chen, C-H; Yang, L-M; Lee, K-H
MLA Citation
Sun, I-C, Wang, H-K, Kashiwada, Y, Shen, J-K, Cosentino, LM, Chen, C-H, Yang, L-M, and Lee, K-H. "Anti-AIDS agents. 34. Synthesis and structure-activity relationships of betulin derivatives as anti-HIV agents." Journal of Medicinal Chemistry 41.23 (1998): 4648-4657.
PMID
9804704
Source
scival
Published In
Journal of Medicinal Chemistry
Volume
41
Issue
23
Publish Date
1998
Start Page
4648
End Page
4657
DOI
10.1021/jm980391g

Noncytolytic CD8 T cell-mediated suppression of HIV replication.

Authors
Greenberg, ML; Lacey, SF; Chen, CH; Bolognesi, DP; Weinhold, KJ
MLA Citation
Greenberg, ML, Lacey, SF, Chen, CH, Bolognesi, DP, and Weinhold, KJ. "Noncytolytic CD8 T cell-mediated suppression of HIV replication." Springer Semin Immunopathol 18.3 (1997): 355-369. (Review)
PMID
9089954
Source
pubmed
Published In
Springer seminars in immunopathology
Volume
18
Issue
3
Publish Date
1997
Start Page
355
End Page
369

Anti-AIDS agents - XXVII. Synthesis and anti-HIV activity of betulinic acid and dihydrobetulinic acid derivatives

Two series of lupane-type triterpenoic acid derivatives were synthesized and evaluated for their inhibitory activity against HIV-1 replication in acutely infected H9 cells, based on the fact that betulinic acid (1) and dihydrobetulinic acid (9) were identified as anti-HIV agents. Among the derivatives, 3-O-(3',3'-dimethylsuccinyl)-betulinic acid (3) and 3-O-(3',3'-dimethylsuccinyl)-dihydrobetulinic acid (11) both demonstrated extremely potent inhibitory activity with EC50 values of <3.5 x 10-4 μM, and remarkable in vitro therapeutic index (TI) values of 20,000 and 14,000, respectively. 3-O-(3',3'-dimethylglutaryl)-betulinic acid (4) and -dihydrobetulinic acid (12), 3-O-diglycolyl-betulinic acid (5) and -dihydrobetulinic acid (13) and 3-O-glutaryl-betulinic acid (6) were also potent inhibitors of HIV replication with EC50 values ranging from 0.04 to 2.3 x 10-3 μM and TI values from 292 to 2344. In addition, compounds 11 and 12 were also active against HIV replication in a monocyte cell line and in peripheral blood mononuclear cells. Our in vitro assay indicated that these compounds are not inhibitors of HIV-1 reverse transcriptase, whereas they inhibited syncytia formation completely in a concentration range of 20-40 μg/mL. However, 3-O-(2',2'-dimethylsuccinyl)-betulinic acid (2) was also found to be an inhibitor of HIV-induced membrane fusion with an IC100 value of 20 μg/mL, though it displayed significantly lower anti-HIV activity than foregoing compounds with an EC50 value of 2.7 μM and TI of 6.7. Further study is underway to determine the mechanisms of action of these compounds.

Authors
Hashimoto, F; Kashiwada, Y; Cosentino, LM; Chen, C-H; Garrett, PE; Lee, K-H
MLA Citation
Hashimoto, F, Kashiwada, Y, Cosentino, LM, Chen, C-H, Garrett, PE, and Lee, K-H. "Anti-AIDS agents - XXVII. Synthesis and anti-HIV activity of betulinic acid and dihydrobetulinic acid derivatives." Bioorganic and Medicinal Chemistry 5.12 (1997): 2133-2143.
PMID
9459011
Source
scival
Published In
Bioorganic & Medicinal Chemistry
Volume
5
Issue
12
Publish Date
1997
Start Page
2133
End Page
2143
DOI
10.1016/S0968-0896(97)00158-2

Betulinic acid and dihydrobetulinic acid derivatives as potent anti-HIV agents

Authors
Kashiwada, Y; Hashimoto, F; Cosentino, LM; Chen, C-H; Garrett, PE; Lee-, KH
MLA Citation
Kashiwada, Y, Hashimoto, F, Cosentino, LM, Chen, C-H, Garrett, PE, and Lee-, KH. "Betulinic acid and dihydrobetulinic acid derivatives as potent anti-HIV agents." Journal of Medicinal Chemistry 39.5 (1996): 1016-1017.
PMID
8676334
Source
scival
Published In
Journal of Medicinal Chemistry
Volume
39
Issue
5
Publish Date
1996
Start Page
1016
End Page
1017
DOI
10.1021/jm950922q

Oligoclonal CD8 lymphocytes from persons with asymptomatic human immunodeficiency virus (HIV) type 1 infection inhibit HIV-1 replication.

CD8 lymphocytes from asymptomatic human immunodeficiency virus (HIV) type 1-infected patients can suppress virus production from infected CD4 cells. Suppressive activity is separate and distinct from cytotoxic T lymphocyte (CTL) reactivities and is likely mediated by a soluble factor(s). The majority of HIV-1 suppression studies have been done in the context of bulk CD8 cell cultures. In this study, viral suppression was characterized by clonal populations of CD8 cells derived from HIV-1-infected patients. Most of the suppressive clones were devoid of detectable CTL reactivity against env-, gag-, pol-, and nef-expressing targets. Among the suppressive clones derived from an individual patient, a marked heterogeneity was evident with respect to phenotypic markers, cytokine production, and T cell receptor V beta expression. These results suggest that noncytolytic virus suppression is oligoclonal in nature. Clones provide tools for future studies aimed at understanding the mechanism of suppression and identifying the suppressive factor.

Authors
Toso, JF; Chen, CH; Mohr, JR; Piglia, L; Oei, C; Ferrari, G; Greenberg, ML; Weinhold, KJ
MLA Citation
Toso, JF, Chen, CH, Mohr, JR, Piglia, L, Oei, C, Ferrari, G, Greenberg, ML, and Weinhold, KJ. "Oligoclonal CD8 lymphocytes from persons with asymptomatic human immunodeficiency virus (HIV) type 1 infection inhibit HIV-1 replication." J Infect Dis 172.4 (October 1995): 964-973.
PMID
7561217
Source
pubmed
Published In
Journal of Infectious Diseases
Volume
172
Issue
4
Publish Date
1995
Start Page
964
End Page
973

A molecular clasp in the human immunodeficiency virus (HIV) type 1 TM protein determines the anti-HIV activity of gp41 derivatives: implication for viral fusion.

We have previously reported that synthetic peptides representing the leucine zipper domain (DP107) and a second putative helical domain (DP178) of human immunodeficiency virus type 1 (HIV-1) gp41 exhibit potent anti-HIV activity. In this study we have used soluble recombinant forms of gp41 to provide evidence that the DP178 peptide and the DP178 region of gp41 associate with a distal site on the gp41 transmembrane protein whose interactive structure is influenced by the leucine zipper (DP107) motif. We also observed that a single coiled-coil-disrupting mutation in the leucine zipper domain transformed the recombinant gp41 protein from an inactive to an active inhibitor of HIV-1 fusion and infectivity, which may be related to that finding. We speculate that this transformation results from liberation of the potent DP178-related sequence from a molecular clasp with a leucine zipper, DP107, determinant. The results are discussed in the context of two distinct conformations for the gp41 molecule and possible involvement of these two domains in structural transitions associated with HIV-1-mediated fusion. The results are also interpreted to suggest that the anti-HIV activity of the various gp41 derivatives (peptides and recombinant proteins) may be due to their ability to form complexes with viral gp41 and interfere with its fusogenic processes.

Authors
Chen, CH; Matthews, TJ; McDanal, CB; Bolognesi, DP; Greenberg, ML
MLA Citation
Chen, CH, Matthews, TJ, McDanal, CB, Bolognesi, DP, and Greenberg, ML. "A molecular clasp in the human immunodeficiency virus (HIV) type 1 TM protein determines the anti-HIV activity of gp41 derivatives: implication for viral fusion." J Virol 69.6 (June 1995): 3771-3777.
PMID
7538176
Source
pubmed
Published In
Journal of virology
Volume
69
Issue
6
Publish Date
1995
Start Page
3771
End Page
3777

SUPPRESSION OF HIV-1 REPLICATION BY PRIMARY AND TRANSFORMED CD8 CELLS

Authors
LACEY, SF; CHEN, CH; WEINHOLD, RJ; GREENBERG, ML
MLA Citation
LACEY, SF, CHEN, CH, WEINHOLD, RJ, and GREENBERG, ML. "SUPPRESSION OF HIV-1 REPLICATION BY PRIMARY AND TRANSFORMED CD8 CELLS." 1995.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
11
Publish Date
1995
Start Page
S133
End Page
S133

Structural rearrangements in the transmembrane glycoprotein after receptor binding.

Authors
Matthews, TJ; Wild, C; Chen, CH; Bolognesi, DP; Greenberg, ML
MLA Citation
Matthews, TJ, Wild, C, Chen, CH, Bolognesi, DP, and Greenberg, ML. "Structural rearrangements in the transmembrane glycoprotein after receptor binding." Immunol Rev 140 (August 1994): 93-104. (Review)
PMID
7821930
Source
pubmed
Published In
Immunological Reviews
Volume
140
Publish Date
1994
Start Page
93
End Page
104

CD8+T-LYMPHOCYTE-MEDIATED INHIBITION OF HIV-1 LTR TRANSCRIPTION

Authors
CHEN, CH; WEINHOLD, KJ; BARTLETT, JA; BOLOGNESI, DP; GREENBERG, ML
MLA Citation
CHEN, CH, WEINHOLD, KJ, BARTLETT, JA, BOLOGNESI, DP, and GREENBERG, ML. "CD8+T-LYMPHOCYTE-MEDIATED INHIBITION OF HIV-1 LTR TRANSCRIPTION." August 1994.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
10
Publish Date
1994
Start Page
S36
End Page
S36

Anti-AIDS agents. 15. Synthesis and anti-HIV activity of dihydroseselins and related analogs

Forty-two dihydroseselins based on the structure of suksdorfin (1) were synthesized in order to evaluate their anti-HIV activity. These synthetic derivatives include 3',4'-di-O-acyl- and 3'- or 4'-O-acyl-cis-dihydroseselins (8-21) and 3',4'-trans-dihydroseselins with O-acyl and/or O-alkyl groups at the 3' and 4' positions (6, 22-43). Two 4'-azido (44, 45) and three 4'- alkylamido (46, 48, 49) derivatives were also prepared. By using optically pure reagents, three pairs of diastereoisomers were synthesized and separated as optically pure compounds (14, 15; 16, 17; 38, 39). Together with the above synthetic derivatives, seselin (3) and (±)-cis-(4), (+)-cis- (5), and (±)- trans-dihydroseselin-3',4'-diol (7) were also tested for their in vitro anti- HIV activity. An optically pure compound, 3',4'-di-O-(-)-camphanoyl-(+)-cis- khellactone (16), showed potent inhibitory activity and remarkable selectivity against HIV replication. The EC50 value and in vitro therapeutic index (TI) of 16 are 4 x 10-4 μM and 136 719, respectively, which are better than those shown by AZT in the same assay. In addition, compound 16 is also active against HIV replication in a monocytic cell line and in peripheral blood mononuclear cells (PBMCs). Our in vitro assay indicated that, like compound 1, compound 16 is not an inhibitor of HIV-1 reverse transcriptase. Moreover, the anti-HIV activity of 16 is stereoselective as its three diastereoisomers (17, 38, 39) are at least 10 000 times less active. Since other synthetic dihydroseselin derivatives with different substituents or without any substituents are inactive or are active only at much higher concentrations, the antiviral potency of 16 could be associated with the camphanoyl moieties of its structure. Therefore, compound 16 represents a unique coumarin structure with promising anti-HIV activity.

Authors
Huang, L; Kashiwada, Y; Cosentino, LM; Fan, S; Chen, C-H; McPhail, AT; Fujioka, T; Mihashi, K; Lee, K-H
MLA Citation
Huang, L, Kashiwada, Y, Cosentino, LM, Fan, S, Chen, C-H, McPhail, AT, Fujioka, T, Mihashi, K, and Lee, K-H. "Anti-AIDS agents. 15. Synthesis and anti-HIV activity of dihydroseselins and related analogs." Journal of Medicinal Chemistry 37.23 (1994): 3947-3955.
PMID
7525962
Source
scival
Published In
Journal of Medicinal Chemistry
Volume
37
Issue
23
Publish Date
1994
Start Page
3947
End Page
3955
DOI
10.1021/jm00049a014

CD8+ T lymphocyte-mediated inhibition of HIV-1 long terminal repeat transcription: a novel antiviral mechanism.

HIV-1 infection evokes a vigorous antiviral response that may participate in resolving the initial peak of plasma viremia and maintenance of the asymptomatic state. CD8+ T lymphocytes of HIV-1-infected individuals play a critical role in the cellular anti-HIV response. In agreement with previous reports, we observed a potent suppressive effect on HIV-1 production from autologous CD4+ T lymphocytes by CD8+ T lymphocytes from asymptomatic HIV-1-infected individuals. To elucidate the mechanism(s) of the nonlytic suppressive antiviral activity, we examined the effect of CD8+ T lymphocytes on the transcriptional activity of the HIV-1 promoter (HIV-LTR). CD8+ lymphocytes from HIV-1-infected asymptomatic individuals suppressed tat-mediated HIV-LTR transcription in CD4+ lymphocytes. HIV-LTR transcriptional activity was suppressed by CD8 lymphocytes to an extent similar to tat-mediated transcription whereas CMV immediate early gene promoter activity was not affected. In contrast to the suppressive effect seen with CD8+ lymphocytes from HIV-1-infected individuals, CD8+ lymphocytes from uninfected individuals did not significantly inhibit tat-mediated or HIV-LTR transcription. The transcriptional inhibitory activity was not MHC class I restricted and could be mediated by a soluble factor(s). Supernatants from some CD8+ T lymphocyte cultures from HIV-1+ individuals exerted an inhibitory effect on tat-mediated HIV-LTR transcription comparable to that seen with CD8+ cells. In conclusion, CD8+ lymphocytes from asymptomatic HIV-1+ individuals could suppress virus production by inhibiting HIV-1 gene expression.(ABSTRACT TRUNCATED AT 250 WORDS)

Authors
Chen, CH; Weinhold, KJ; Bartlett, JA; Bolognesi, DP; Greenberg, ML
MLA Citation
Chen, CH, Weinhold, KJ, Bartlett, JA, Bolognesi, DP, and Greenberg, ML. "CD8+ T lymphocyte-mediated inhibition of HIV-1 long terminal repeat transcription: a novel antiviral mechanism." AIDS Res Hum Retroviruses 9.11 (November 1993): 1079-1086.
PMID
8312050
Source
pubmed
Published In
AIDS Research and Human Retroviruses
Volume
9
Issue
11
Publish Date
1993
Start Page
1079
End Page
1086
DOI
10.1089/aid.1993.9.1079

CD8+ T-LYMPHOCYTES FROM ASYMPTOMATIC HIV-1 INFECTED INDIVIDUALS SUPPRESS TAT-MEDIATED HIV-1 LTR TRANSCRIPTION

Authors
CHEN, CH; WEINHOLD, KJ; BARTLETT, JA; MACDOUGALL, MJ; GREENBERG, ML
MLA Citation
CHEN, CH, WEINHOLD, KJ, BARTLETT, JA, MACDOUGALL, MJ, and GREENBERG, ML. "CD8+ T-LYMPHOCYTES FROM ASYMPTOMATIC HIV-1 INFECTED INDIVIDUALS SUPPRESS TAT-MEDIATED HIV-1 LTR TRANSCRIPTION." March 29, 1993.
Source
wos-lite
Published In
Journal of Cellular Biochemistry
Publish Date
1993
Start Page
75
End Page
75

The role of cytoplasmic deoxycytidine kinase in the mitochondrial effects of the anti-human immunodeficiency virus compound, 2′,3′-dideoxycytidine

2′,3′-Dideoxycytidine (ddC) is a potent inhibitor of human immunodeficiency virus replication in vitro and shows beneficial effects in AIDS therapy. The compound inhibits mitochondrial DNA (mtDNA) synthesis at a clinically relevant concentration, which could be responsible for the side effects of ddC observed in the clinic. Thymidine (dThd), one of the substrates of mitochondrial deoxypyrimidine kinase (dPyd kinase), was not able to reverse the mitochondrial toxicity of ddC in CEM cells. Furthermore, the cytoplasmic deoxycytidine kinase (dCyd kinase)-deficient CEM cells were highly resistant to the mitochondrial toxicity of ddC. These data suggest a critical role for cytoplasmic dCyd kinase in the mitochondrial toxicity of ddC. The metabolites of ddC, but not ddC itself, were able to inhibit mtDNA synthesis in isolated mitochondria. The potency of the inhibitory effect was in the order of ddCTP > ddCDP > ddCMP > ddC. The lack of inhibition by ddC of mtDNA synthesis could be due to the inefficient ddC phosphorylation in mitochondria. Although the mitochondrial dPyd kinase was reported to phosphorylate ddC, the phosphorylation of ddC in isolated mitochondria was not detectable. The data suggest that ddC is phosphorylated to ddCTP in the cytoplasm and then transported into mitochondria to exert its inhibitory effect on mtDNA synthesis.

Authors
Chen, C-H; Cheng, Y-C
MLA Citation
Chen, C-H, and Cheng, Y-C. "The role of cytoplasmic deoxycytidine kinase in the mitochondrial effects of the anti-human immunodeficiency virus compound, 2′,3′-dideoxycytidine." Journal of Biological Chemistry 267.5 (1992): 2856-2859.
PMID
1310674
Source
scival
Published In
The Journal of biological chemistry
Volume
267
Issue
5
Publish Date
1992
Start Page
2856
End Page
2859

Effect of anti-human immunodeficiency virus nucleoside analogs on mitochondrial DNA and its implication for delayed toxicity

The anti-human immunodeficiency virus (-HIV) nucleoside analogs azidothymidine (AZT), dideoxycytidine (ddC), dideoxyinosine (ddI), dideoxydidehydrothymidine (D4T), and dideoxydidehydrocytidine (D4C) and the anticancer drug cytosine arabinoside (AraC) were compared for their effects on the mitochondnal DNA (mtDNA) content in a human lymphoblastoid cell line, CEM. The potency of these compounds in reducing mtDNA content was in the order of ddC > D4C > D4T > AZT > ddI. AraC did not have a significant effect on mtDNA content. All of the compounds tested, except AraC, stimulated lactic acid production at concentrations that inhibited mtDNA synthesis. The action of ddC and ddI occurred at concentrations that did not affect cell growth significantly in 4 days but retarded cell growth by day 6. D4T and D4C decreased mtDNA content by 50% at doses lower than those that inhibited cell growth by 50% in 4 days (ID50). However, AZT required a dose higher than the ID50 to exert similar effects on mtDNA content. The decrease of mtDNA content caused by ddC also occurred in nerve growth factor-treated PC12 cells, which differentiate to neuron-like cells upon treatment with nerve growth factor. The preferential inhibition of mtDNA, compared with cell growth, by some of these anti-HIV nucleoside analogs correlates well with their ability to cause drug-limiting delayed toxicity, such as peripheral neuropathy, in patients. These data suggest that the selective mitochondrial toxicity could be responsible for the delayed toxicity caused by these anti-HIV analogs.

Authors
Chen, C-H; Vazquez-Padua, M; Cheng, Y-C
MLA Citation
Chen, C-H, Vazquez-Padua, M, and Cheng, Y-C. "Effect of anti-human immunodeficiency virus nucleoside analogs on mitochondrial DNA and its implication for delayed toxicity." Molecular Pharmacology 39.5 (1991): 625-628.
PMID
1851960
Source
scival
Published In
Molecular Pharmacology
Volume
39
Issue
5
Publish Date
1991
Start Page
625
End Page
628

DNA polymerases versus HIV reverse transcriptase in AIDS therapy

Authors
Cheng, Y-C; Gao, W-Y; Chen, C-H; Vazquez-Padua, M; Starnes, MC
MLA Citation
Cheng, Y-C, Gao, W-Y, Chen, C-H, Vazquez-Padua, M, and Starnes, MC. "DNA polymerases versus HIV reverse transcriptase in AIDS therapy." Annals of the New York Academy of Sciences 616 (1990): 217-223.
PMID
1706570
Source
scival
Published In
Annals of the New York Academy of Sciences
Volume
616
Publish Date
1990
Start Page
217
End Page
223

Delayed cytotoxicity and selective loss of mitochondrial DNA in cells treated with the anti-human immunodeficiency virus compound 2',3'-dideoxycytidine

The compound 2',3'-dideoxycytidine (ddC) is a potent inhibitor of human immunodeficiency virus replication in vitro and is currently in clinical trials for treatment of acquired immunodeficiency syndrome. The compound was found to exert delayed cytotoxicity against Molt-4F cells, a human T lymphoblastic cell line. At a concentration as low as 0.1 μM, the doubling time of the cells was increased after 8 days of ddC treatment. This concentration is 5-fold lower than plasma levels reached in clinical trials. The cells finally died after a 2-week exposure to 0.1 or 0.2 μM ddC. The delayed cytotoxicity was not due to a greater accumulation of 2',3'-dideoxycytidine triphosphate in cells with longer exposure to the compound. The cellular content of mitochondrial DNA was found to decrease and the rate of glycolysis was found to increase with continuous exposure of cells to ddC. The mitochondrial toxicity and cell growth inhibition were reversed when ddC was removed. The reduction in cellular content of mitochondrial DNA caused by ddC may partially explain the delayed toxicity observed in acquired immunodeficiency syndrome patients treated with the drug.

Authors
Chen, C-H; Cheng, Y-C
MLA Citation
Chen, C-H, and Cheng, Y-C. "Delayed cytotoxicity and selective loss of mitochondrial DNA in cells treated with the anti-human immunodeficiency virus compound 2',3'-dideoxycytidine." Journal of Biological Chemistry 264.20 (1989): 11934-11937.
PMID
2745424
Source
scival
Published In
Journal of Biological Chemistry
Volume
264
Issue
20
Publish Date
1989
Start Page
11934
End Page
11937
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