由于R5亚型HIV-1在感染早期占支配地位，CCR5的拮抗剂可以作为一个有效的抗逆转录病毒以及预防病毒感染的试剂。maraviroc是一种潜在的、特异性的、非竞争性的CCRS受体拮抗剂，可以抑制HIVgp120与辅助受体的结合。2007年8月6日，Maraviroc（商品名Selzentry）被批准用于和其他抗逆转录病毒药物联合应用治疗CCR5-tropic HIV1型成年病人(FDA批准了Pfizer的抗HIV新药)。但是，HIV-1逐渐出现了抗Maraviroc的现象，对CCR5拮抗剂的发现提出了极大的挑战。近日，香港大学的Zhiwei Chen及其同事研究发现了一个CCR5拮抗剂TD-0680的一个新奇的机制，它可以抵抗HIV-1的入侵，细胞介导的感染及耐药突变种。相关论文发表在3月23的美国《生化周刊》（Journal of Biological Chemistry）上。
本次实验研究了一个新奇的小分子CCR5拮抗剂TD-0680的特异性、效能以及潜在的作用机理。TD-0232是TD-0680的前体，当与TD-0232比较时，TD-0680在抵御R5亚型HIV-1及SIV病毒时表现出了强大的效能。在次纳摩尔（subnanomolar）的范围(0.09-2.29 nM)，TAK-779具有EC50值（EC50即半最大效应浓度，是指能引起50%最大效应的浓度，它是药物安全性指标）。研究发现，TD-0680对阻遏包膜介导的细胞融合，细胞介导的病毒运输及TAK-779/Maraviroc抗性HIV-1变种也有强大的抵御作用。有趣的是，尽管TD-0232和TD-0680结合在相似的CCR5跨膜口袋，它们的功能完全不同。位点特异性突变、合并用药及抗体阻断化验鉴定发现：除了结合在跨膜口袋，TD-0680特异性的三维结构可以与CCR5的ECL2区结合，因此阻断了病毒与其辅助受体有效的相互作用。TD-0680抵御CD4依赖好热CD4不依赖的SIV菌株及CCR5模型的分子对接分析实验表明，TD-0680同样具有相同的效能。
因此，TD-0680可以发展为一个临床抗HIV-1剂,或者是作为一个局部杀菌剂来预防R5亚型HIV-1的性传播途经。（生物谷Deepblue编译）
doi: 10.1074/jbc.M112.354084
PMC:
PMID:
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 Chi Kong Lau, Xiaofan Lu, Li Liu, Allen Ka Loon Cheung, Zhiwu Tan, Jenny Ng, Jianguo Liang, Haibo Wang, Sai Kam Li, Bojian Zheng, Ben Li, Li Chen and Zhiwei Chen.
Regardless of the route of transmission, R5-tropic HIV-1 predominates early in infection, rendering 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 to its prodrug TD-0232, the FDA-approved CCR5 antagonist Maraviroc, and TAK-779 with EC50 values in the subnanomolar range (0.09-2.29 nM).Importantly, TD-0680 was equally potent at blocking envelope-mediated cell-cell fusion, 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 (TM) 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 TM pocket, the unique exo-configuration of this molecule protrudes and sterically blocks access to the 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.
