Allen Ka Loon Cheung

Publications (2)9.55 Total impact

• Source

  Available from: Zhiwei Wu

  Article: CCR5 antagonist TD-0680 uses a novel mechanism for enhanced potency against HIV-1 entry, cell-mediated infection, and a resistant variant.

  Yuanxi Kang, Zhiwei Wu, Terrence C K Lau, Xiaofan Lu, Li Liu, Allen K L Cheung, Zhiwu Tan, Jenny Ng, Jianguo Liang, Haibo Wang, Saikam Li, Bojian Zheng, Ben Li, Li Chen, Zhiwei Chen
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  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.
  Journal of Biological Chemistry 03/2012; 287(20):16499-509. · 4.77 Impact Factor
• Article: A potent CCR5 antagonist TD-0680 against HIV-1 infection, cell-to-cell transmission and a TAK-779/Maraviroc-resistant variant

  Yuanxi Kang, Xiaofan Lu, Terrence Chi Kong Lau, Li Liu, Allen Ka Loon Cheung, Zhiwu Tan, Jianguo Liang, Haibo Wang, Sai Kam Li, Bojian Zheng, Li Chen, Zhiwei Wu, Zhiwei Chen
  Journal of Biological Chemistry 03/2012; · 4.77 Impact Factor