Bristol-Myers Squibb, Research and Development, Wallingford, Connecticut, USA.
Antimicrob Agents Chemother. 2013 Sep;57(9):4172-80. doi: 10.1128/AAC.00513-13. Epub 2013 Jun 17.
BMS-626529 is a novel small-molecule HIV-1 attachment inhibitor active against both CCR5- and CXCR4-tropic viruses. BMS-626529 functions by preventing gp120 from binding to CD4. A prodrug of this compound, BMS-663068, is currently in clinical development. As a theoretical resistance pathway to BMS-663068 could be the development of a CD4-independent phenotype, we examined the activity of BMS-626529 against CD4-independent viruses and investigated whether resistance to BMS-626529 could be associated with a CD4-independent phenotype. Finally, we evaluated whether cross-resistance exists between BMS-626529 and other HIV-1 entry inhibitors. Two laboratory-derived envelopes with a CD4-independent phenotype (one CXCR4 tropic and one CCR5 tropic), five envelopes from clinical isolates with preexisting BMS-626529 resistance, and several site-specific mutant BMS-626529-resistant envelopes were examined for their dependence on CD4 for infectivity or susceptibility to BMS-626529. Viruses resistant to other entry inhibitors (enfuvirtide, maraviroc, and ibalizumab) were also examined for susceptibility to BMS-626529. Both CD4-independent laboratory isolates retained sensitivity to BMS-626529 in CD4(-) cells, while HIV-1 envelopes from viruses resistant to BMS-626529 exhibited no evidence of a CD4-independent phenotype. BMS-626529 also exhibited inhibitory activity against ibalizumab- and enfuvirtide-resistant envelopes. While there appeared to be some association between maraviroc resistance and reduced susceptibility to BMS-626529, an absolute correlation cannot be presumed, since some CCR5-tropic maraviroc-resistant envelopes remained sensitive to BMS-626529. Clinical use of the prodrug BMS-663068 is unlikely to promote resistance via generation of CD4-independent virus. No cross-resistance between BMS-626529 and other HIV entry inhibitors was observed, which could allow for sequential or concurrent use with different classes of entry inhibitors.
BMS-626529 是一种新型的 HIV-1 附着抑制剂，对 CCR5 和 CXCR4 趋化因子的病毒均具有活性。BMS-626529 通过阻止 gp120 与 CD4 结合而发挥作用。该化合物的前药 BMS-663068 目前正在临床开发中。由于 BMS-663068 的一种理论上的耐药途径可能是产生 CD4 非依赖性表型，因此我们研究了 BMS-626529 对 CD4 非依赖性病毒的活性，并探讨了对 BMS-626529 的耐药性是否与 CD4 非依赖性表型相关。最后，我们评估了 BMS-626529 与其他 HIV-1 进入抑制剂之间是否存在交叉耐药性。我们检测了两个具有 CD4 非依赖性表型的实验室衍生包膜（一个 CXCR4 嗜性，一个 CCR5 嗜性），五个具有 BMS-626529 预先存在耐药性的临床分离株包膜，以及几个针对 BMS-626529 的位点特异性突变包膜，以检测它们对感染性或对 BMS-626529 的敏感性是否依赖 CD4。还检测了对其他进入抑制剂（恩夫韦肽、马拉韦罗和依替巴肽）耐药的病毒对 BMS-626529 的敏感性。对 BMS-626529 耐药的 HIV-1 包膜在 CD4(-)细胞中仍然对 BMS-626529 敏感，而对 BMS-626529 耐药的病毒产生的 HIV-1 包膜则没有 CD4 非依赖性表型的证据。BMS-626529 对依替巴肽和恩夫韦肽耐药的包膜也表现出抑制活性。虽然马拉韦罗耐药与对 BMS-626529 的敏感性降低之间似乎存在一定的相关性，但不能假定存在绝对相关性，因为一些 CCR5 嗜性马拉韦罗耐药的包膜仍然对 BMS-626529 敏感。BMS-663068 的前药的临床应用不太可能通过产生 CD4 非依赖性病毒来促进耐药性。我们没有观察到 BMS-626529 与其他 HIV 进入抑制剂之间的交叉耐药性，这可能允许与不同类别的进入抑制剂进行序贯或同时使用。
