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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

TitleCCR5 antagonist TD-0680 uses a novel mechanism for enhanced potency against HIV-1 entry, cell-mediated infection, and a resistant variant
Authors
Issue Date2012
PublisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/
Citation
Journal Of Biological Chemistry, 2012, v. 287 n. 20, p. 16499-16509 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/152765
ISSN
2015 Impact Factor: 4.258
2015 SCImago Journal Rankings: 3.151
ISI Accession Number ID
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.

References

 

DC FieldValueLanguage
dc.contributor.authorKang, Yen_HK
dc.contributor.authorWu, Zen_HK
dc.contributor.authorLau, TCKen_HK
dc.contributor.authorLu, Xen_HK
dc.contributor.authorLiu, Len_HK
dc.contributor.authorCheung, AKLen_HK
dc.contributor.authorTan, Zen_HK
dc.contributor.authorNg, Jen_HK
dc.contributor.authorLiang, Jen_HK
dc.contributor.authorWang, Hen_HK
dc.contributor.authorLi, Sen_HK
dc.contributor.authorZheng, Ben_HK
dc.contributor.authorLi, Ben_HK
dc.contributor.authorChen, Len_HK
dc.contributor.authorChen, Zen_HK
dc.date.accessioned2012-07-16T09:47:57Z-
dc.date.available2012-07-16T09:47:57Z-
dc.date.issued2012en_HK
dc.identifier.citationJournal Of Biological Chemistry, 2012, v. 287 n. 20, p. 16499-16509en_HK
dc.identifier.issn0021-9258en_HK
dc.identifier.urihttp://hdl.handle.net/10722/152765-
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.en_HK
dc.languageengen_US
dc.publisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/en_HK
dc.relation.ispartofJournal of Biological Chemistryen_HK
dc.titleCCR5 antagonist TD-0680 uses a novel mechanism for enhanced potency against HIV-1 entry, cell-mediated infection, and a resistant varianten_HK
dc.typeArticleen_HK
dc.identifier.emailLiu, L: liuli71@hkucc.hku.hken_HK
dc.identifier.emailWang, H: haibo@hku.hken_HK
dc.identifier.emailZheng, B: bzheng@hkucc.hku.hken_HK
dc.identifier.emailChen, Z: zchenai@hku.hken_HK
dc.identifier.authorityLiu, L=rp00268en_HK
dc.identifier.authorityWang, H=rp00279en_HK
dc.identifier.authorityZheng, B=rp00353en_HK
dc.identifier.authorityChen, Z=rp00243en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1074/jbc.M112.354084en_HK
dc.identifier.pmid22447925-
dc.identifier.scopuseid_2-s2.0-84860859266en_HK
dc.identifier.hkuros200531en_US
dc.identifier.hkuros206331-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-84860859266&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume287en_HK
dc.identifier.issue20en_HK
dc.identifier.spage16499en_HK
dc.identifier.epage16509en_HK
dc.identifier.eissn1083-351X-
dc.identifier.isiWOS:000304030900040-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridKang, Y=54793057300en_HK
dc.identifier.scopusauthoridWu, Z=55204054600en_HK
dc.identifier.scopusauthoridLau, TCK=36981810500en_HK
dc.identifier.scopusauthoridLu, X=35215493700en_HK
dc.identifier.scopusauthoridLiu, L=35784425200en_HK
dc.identifier.scopusauthoridCheung, AKL=24390378000en_HK
dc.identifier.scopusauthoridTan, Z=55214770900en_HK
dc.identifier.scopusauthoridNg, J=55214532500en_HK
dc.identifier.scopusauthoridLiang, J=55214500600en_HK
dc.identifier.scopusauthoridWang, H=36143443600en_HK
dc.identifier.scopusauthoridLi, S=24479327400en_HK
dc.identifier.scopusauthoridZheng, B=7201780588en_HK
dc.identifier.scopusauthoridLi, B=7410078454en_HK
dc.identifier.scopusauthoridChen, L=55214792700en_HK
dc.identifier.scopusauthoridChen, Z=35271180800en_HK

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