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Article: CCR5 antagonist TD-0680 uses a novel mechanism for enhanced potency against HIV-1 entry, cell-mediated infection, and a resistant variant
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TitleCCR5 antagonist TD-0680 uses a novel mechanism for enhanced potency against HIV-1 entry, cell-mediated infection, and a resistant variant
 
AuthorsKang, Y2
Wu, Z1
Lau, TCK3
Lu, X2
Liu, L2
Cheung, AKL2
Tan, Z2
Ng, J2
Liang, J2
Wang, H2
Li, S3
Zheng, B2
Li, B5
Chen, L5
Chen, Z2 4
 
Issue Date2012
 
PublisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/
 
CitationJournal Of Biological Chemistry, 2012, v. 287 n. 20, p. 16499-16509 [How to Cite?]
DOI: http://dx.doi.org/10.1074/jbc.M112.354084
 
AbstractRegardless of the route of transmission, R5-tropic HIV-1 predominates early in infection, rendering C-C chemokine receptor type 5 (CCR5) antagonists as attractive agents not only for antiretroviral therapy but also for prevention. Here, we report the specificity, potency, and underlying mechanism of action of a novel small molecule CCR5 antagonist, TD-0680. TD-0680 displayed the greatest potency against a diverse group of R5-tropic HIV-1 and SIV strains when compared with its prodrug, TD-0232, the Food and Drug Administration-approved CCR5 antagonist Maraviroc, and TAK-779, with EC 50 values in the subnanomolar range (0.09-2.29 nM). Importantly, TD-0680 was equally potent at blocking envelope-mediated cell-cell fusion and cell-mediated viral transmission as well as the replication of a TAK-779/Maraviroc-resistant HIV-1 variant. Interestingly, TD-0232 and TD-0680 functioned differently despite binding to a similar transmembrane pocket of CCR5. Site-directed mutagenesis, drug combination, and antibody blocking assays identified a novel mechanism of action of TD-0680. In addition to binding to the transmembrane pocket, the unique exo configuration of this molecule protrudes and sterically blocks access to the extracellular loop 2 (ECL2) region of CCR5, thereby interrupting the interaction between virus and its co-receptor more effectively. This mechanism of action was supported by the observations of similar TD-0680 potency against CD4-dependent and -independent SIV strains and by molecular docking analysis using a CCR5 model. TD-0680, therefore, merits development as an anti-HIV-1 agent for therapeutic purposes and/or as a topical microbicide for the prevention of sexual transmission of R5-tropic HIV-1. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.
 
ISSN0021-9258
2012 Impact Factor: 4.651
2012 SCImago Journal Rankings: 2.723
 
DOIhttp://dx.doi.org/10.1074/jbc.M112.354084
 
ISI Accession Number IDWOS:000304030900040
Funding AgencyGrant Number
HKU-UDF
HKU-LKSFM2008ZX10001-015/2012ZX10001007-009
2012ZX10001-009
NSFC30870124
Funding Information:

This work was supported by HKU-UDF and HKU-LKSFM matching funds to the AIDS Institute, China's 12th Five-year National Science and Technology Mega Projects on the Prevention and Treatment of AIDS 2008ZX10001-015/2012ZX10001007-009, 2012ZX10001-009, and NSFC Grant 30870124.

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorKang, Y
 
dc.contributor.authorWu, Z
 
dc.contributor.authorLau, TCK
 
dc.contributor.authorLu, X
 
dc.contributor.authorLiu, L
 
dc.contributor.authorCheung, AKL
 
dc.contributor.authorTan, Z
 
dc.contributor.authorNg, J
 
dc.contributor.authorLiang, J
 
dc.contributor.authorWang, H
 
dc.contributor.authorLi, S
 
dc.contributor.authorZheng, B
 
dc.contributor.authorLi, B
 
dc.contributor.authorChen, L
 
dc.contributor.authorChen, Z
 
dc.date.accessioned2012-07-16T09:47:57Z
 
dc.date.available2012-07-16T09:47:57Z
 
dc.date.issued2012
 
dc.description.abstractRegardless of the route of transmission, R5-tropic HIV-1 predominates early in infection, rendering C-C chemokine receptor type 5 (CCR5) antagonists as attractive agents not only for antiretroviral therapy but also for prevention. Here, we report the specificity, potency, and underlying mechanism of action of a novel small molecule CCR5 antagonist, TD-0680. TD-0680 displayed the greatest potency against a diverse group of R5-tropic HIV-1 and SIV strains when compared with its prodrug, TD-0232, the Food and Drug Administration-approved CCR5 antagonist Maraviroc, and TAK-779, with EC 50 values in the subnanomolar range (0.09-2.29 nM). Importantly, TD-0680 was equally potent at blocking envelope-mediated cell-cell fusion and cell-mediated viral transmission as well as the replication of a TAK-779/Maraviroc-resistant HIV-1 variant. Interestingly, TD-0232 and TD-0680 functioned differently despite binding to a similar transmembrane pocket of CCR5. Site-directed mutagenesis, drug combination, and antibody blocking assays identified a novel mechanism of action of TD-0680. In addition to binding to the transmembrane pocket, the unique exo configuration of this molecule protrudes and sterically blocks access to the extracellular loop 2 (ECL2) region of CCR5, thereby interrupting the interaction between virus and its co-receptor more effectively. This mechanism of action was supported by the observations of similar TD-0680 potency against CD4-dependent and -independent SIV strains and by molecular docking analysis using a CCR5 model. TD-0680, therefore, merits development as an anti-HIV-1 agent for therapeutic purposes and/or as a topical microbicide for the prevention of sexual transmission of R5-tropic HIV-1. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.
 
dc.description.naturelink_to_OA_fulltext
 
dc.identifier.citationJournal Of Biological Chemistry, 2012, v. 287 n. 20, p. 16499-16509 [How to Cite?]
DOI: http://dx.doi.org/10.1074/jbc.M112.354084
 
dc.identifier.doihttp://dx.doi.org/10.1074/jbc.M112.354084
 
dc.identifier.eissn1083-351X
 
dc.identifier.epage16509
 
dc.identifier.hkuros200531
 
dc.identifier.hkuros206331
 
dc.identifier.isiWOS:000304030900040
Funding AgencyGrant Number
HKU-UDF
HKU-LKSFM2008ZX10001-015/2012ZX10001007-009
2012ZX10001-009
NSFC30870124
Funding Information:

This work was supported by HKU-UDF and HKU-LKSFM matching funds to the AIDS Institute, China's 12th Five-year National Science and Technology Mega Projects on the Prevention and Treatment of AIDS 2008ZX10001-015/2012ZX10001007-009, 2012ZX10001-009, and NSFC Grant 30870124.

 
dc.identifier.issn0021-9258
2012 Impact Factor: 4.651
2012 SCImago Journal Rankings: 2.723
 
dc.identifier.issue20
 
dc.identifier.pmid22447925
 
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dc.identifier.urihttp://hdl.handle.net/10722/152765
 
dc.identifier.volume287
 
dc.languageeng
 
dc.publisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/
 
dc.publisher.placeUnited States
 
dc.relation.ispartofJournal of Biological Chemistry
 
dc.relation.referencesReferences in Scopus
 
dc.titleCCR5 antagonist TD-0680 uses a novel mechanism for enhanced potency against HIV-1 entry, cell-mediated infection, and a resistant variant
 
dc.typeArticle
 
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Author Affiliations
  1. Nanjing University
  2. The University of Hong Kong
  3. City University of Hong Kong
  4. Shenzhen People's Hospital
  5. null