由于R5亞型HIV-1在感染早期占支配地位，CCR5的拮抗劑可以作為一個有效的抗逆轉(zhuǎn)錄病毒以及預防病毒感染的試劑,。maraviroc是一種潛在的,、特異性的、非競爭性的CCRS受體拮抗劑,，可以抑制HIVgp120與輔助受體的結(jié)合,。2007年8月6日，Maraviroc（商品名Selzentry）被批準用于和其他抗逆轉(zhuǎn)錄病毒藥物聯(lián)合應用治療CCR5-tropic HIV1型成年病人(FDA批準了Pfizer的抗HIV新藥),。但是,，HIV-1逐漸出現(xiàn)了抗Maraviroc的現(xiàn)象，對CCR5拮抗劑的發(fā)現(xiàn)提出了極大的挑戰(zhàn),。近日,，香港大學的Zhiwei Chen及其同事研究發(fā)現(xiàn)了一個CCR5拮抗劑TD-0680的一個新奇的機制，它可以抵抗HIV-1的入侵,，細胞介導的感染及耐藥突變種,。相關論文發(fā)表在3月23的美國《生化周刊》（Journal of Biological Chemistry）上。
本次實驗研究了一個新奇的小分子CCR5拮抗劑TD-0680的特異性,、效能以及潛在的作用機理,。TD-0232是TD-0680的前體，當與TD-0232比較時,，TD-0680在抵御R5亞型HIV-1及SIV病毒時表現(xiàn)出了強大的效能,。在次納摩爾（subnanomolar）的范圍(0.09-2.29 nM)，TAK-779具有EC50值（EC50即半最大效應濃度,，是指能引起50%最大效應的濃度,，它是藥物安全性指標）。研究發(fā)現(xiàn),，TD-0680對阻遏包膜介導的細胞融合，細胞介導的病毒運輸及TAK-779/Maraviroc抗性HIV-1變種也有強大的抵御作用,。有趣的是,，盡管TD-0232和TD-0680結(jié)合在相似的CCR5跨膜口袋，它們的功能完全不同,。位點特異性突變,、合并用藥及抗體阻斷化驗鑒定發(fā)現(xiàn)：除了結(jié)合在跨膜口袋，TD-0680特異性的三維結(jié)構(gòu)可以與CCR5的ECL2區(qū)結(jié)合,，因此阻斷了病毒與其輔助受體有效的相互作用,。TD-0680抵御CD4依賴好熱CD4不依賴的SIV菌株及CCR5模型的分子對接分析實驗表明，TD-0680同樣具有相同的效能,。
因此,，TD-0680可以發(fā)展為一個臨床抗HIV-1劑,或者是作為一個局部殺菌劑來預防R5亞型HIV-1的性傳播途經(jīng),。（生物谷Deepblue編譯）
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.
