title: CCR5 antagonist TD-0680 uses a novel mechanism for enhanced potency against HIV-1 entry, cell-mediated infection, and a resistant variant.
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.
authors.affiliation: AIDS Institute, Department of Microbiology and Research Center for Infection and Immunity, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong SAR, China.
authors.forename: Yuanxi
authors.initials: Y
authors.lastname: Kang
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Wu
authors.forename: Terrence C K
authors.initials: TC
authors.lastname: Lau
authors.forename: Xiaofan
authors.initials: X
authors.lastname: Lu
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Allen K L
authors.initials: AK
authors.lastname: Cheung
authors.forename: Zhiwu
authors.initials: Z
authors.lastname: Tan
authors.forename: Jenny
authors.initials: J
authors.lastname: Ng
authors.forename: Jianguo
authors.initials: J
authors.lastname: Liang
authors.forename: Haibo
authors.initials: H
authors.lastname: Wang
authors.forename: Saikam
authors.initials: S
authors.lastname: Li
authors.forename: Bojian
authors.initials: B
authors.lastname: Zheng
authors.forename: Ben
authors.initials: B
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000577:Amides / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000494:pharmacology*; D001665:Binding Sites; D065100:CCR5 Receptor Antagonists; D002460:Cell Line; D003510:Cyclohexanes / Q000494:pharmacology; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism / Q000635:transmission; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D000077592:Maraviroc; D017433:Protein Structure, Secondary; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D019713:Receptors, CCR5 / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology; D014326:Tropanes / Q000494:pharmacology*; D053586:Virus Internalization / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects* / Q000502:physiology
chemical_list: D000577:Amides; D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D000644:Quaternary Ammonium Compounds; D019713:Receptors, CCR5; D013449:Sulfonamides; C573500:TD-0680; D014230:Triazoles; D014326:Tropanes; C119369:TAK 779; D000077592:Maraviroc