Article: CCR5 antagonist TD-0680 uses a novel mechanism for enhanced potency against HIV-1 entry, cell-mediated infection, and a resistant variant
| Title | CCR5 antagonist TD-0680 uses a novel mechanism for enhanced potency against HIV-1 entry, cell-mediated infection, and a resistant variant | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Authors | Kang, 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 Date | 2012 | ||||||||
| Publisher | American 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?] DOI: http://dx.doi.org/10.1074/jbc.M112.354084 | ||||||||
| Abstract | Regardless 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. | ||||||||
| ISSN | 0021-9258 2011 Impact Factor: 4.773 2011 SCImago Journal Rankings: 0.793 | ||||||||
| DOI | http://dx.doi.org/10.1074/jbc.M112.354084 | ||||||||
| ISI Accession Number ID | WOS:000304030900040
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 | References in Scopus |
| dc.contributor.author | Kang, Y | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| dc.contributor.author | Wu, Z | ||||||||
| dc.contributor.author | Lau, TCK | ||||||||
| dc.contributor.author | Lu, X | ||||||||
| dc.contributor.author | Liu, L | ||||||||
| dc.contributor.author | Cheung, AKL | ||||||||
| dc.contributor.author | Tan, Z | ||||||||
| dc.contributor.author | Ng, J | ||||||||
| dc.contributor.author | Liang, J | ||||||||
| dc.contributor.author | Wang, H | ||||||||
| dc.contributor.author | Li, S | ||||||||
| dc.contributor.author | Zheng, B | ||||||||
| dc.contributor.author | Li, B | ||||||||
| dc.contributor.author | Chen, L | ||||||||
| dc.contributor.author | Chen, Z | ||||||||
| dc.date.accessioned | 2012-07-16T09:47:57Z | ||||||||
| dc.date.available | 2012-07-16T09:47:57Z | ||||||||
| dc.date.issued | 2012 | ||||||||
| dc.description.abstract | Regardless 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.nature | link_to_OA_fulltext | ||||||||
| dc.identifier.citation | Journal 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.doi | http://dx.doi.org/10.1074/jbc.M112.354084 | ||||||||
| dc.identifier.epage | 16509 | ||||||||
| dc.identifier.hkuros | 200531 | ||||||||
| dc.identifier.hkuros | 206331 | ||||||||
| dc.identifier.isi | WOS:000304030900040
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.issn | 0021-9258 2011 Impact Factor: 4.773 2011 SCImago Journal Rankings: 0.793 | ||||||||
| dc.identifier.issue | 20 | ||||||||
| dc.identifier.pmid | 22447925 | ||||||||
| dc.identifier.scopus | eid_2-s2.0-84860859266 | ||||||||
| dc.identifier.spage | 16499 | ||||||||
| dc.identifier.uri | http://hdl.handle.net/10722/152765 | ||||||||
| dc.identifier.volume | 287 | ||||||||
| dc.language | eng | ||||||||
| dc.publisher | American Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/ | ||||||||
| dc.publisher.place | United States | ||||||||
| dc.relation.ispartof | Journal of Biological Chemistry | ||||||||
| dc.relation.references | References in Scopus | ||||||||
| dc.title | CCR5 antagonist TD-0680 uses a novel mechanism for enhanced potency against HIV-1 entry, cell-mediated infection, and a resistant variant | ||||||||
| dc.type | Article |
Author Affiliations
- Nanjing University
- The University of Hong Kong
- City University of Hong Kong
- Shenzhen People's Hospital
- null