Smith Steven J, Pauly Gary T, Akram Aamir, Melody Kevin, Ambrose Zandrea, Schneider Joel P, Hughes Stephen H
*HIV Dynamics and Replication Program, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD; †Chemical Biology Laboratory, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD; ‡Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA; and §Division of Infectious Diseases, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA.
J Acquir Immune Defic Syndr. 2016 Aug 15;72(5):485-91. doi: 10.1097/QAI.0000000000001031.
Rilpivirine (RPV) is the latest non-nucleoside reverse transcriptase inhibitor (NNRTI) to be approved by Food and Drug Administration to combat HIV-1 infections. NNRTIs inhibit the chemical step in viral DNA synthesis by binding to an allosteric site located about 10 Å from the polymerase active site of reverse transcriptase (RT). Although NNRTIs potently inhibit the replication of wild-type HIV-1, the binding site is not conserved, and mutations arise in the binding pocket. Doravirine (DOR) is a new NNRTI in phase III clinical trials.
Using a single round HIV-1 infection assay, we tested RPV and DOR against a broad panel of NNRTI-resistant mutants to determine their respective activities. We also used molecular modeling to determine if the susceptibility profile of each compound was related to how they bind RT.
Several mutants displayed decreased susceptibility to DOR. However, with the exception of E138K, our data suggest that the mutations that reduce the potency of DOR and RPV are non-overlapping. Thus, these 2 NNRTIs have the potential to be used together in combination therapy. We also show that the location at which DOR and RPV bind with the NNRTI binding pocket of RT correlates with the differences in their respective susceptibility to the panel of NNRTI-resistance mutations.
This shows that (1) DOR is susceptible to a number of well-known NNRTI resistance mutations and (2) an understanding of the mutational susceptibilities and binding interactions of NNRTIs with RT could be used to develop pairs of compounds with non-overlapping mutational susceptibilities.
利匹韦林（RPV）是美国食品药品监督管理局批准用于对抗HIV-1感染的最新非核苷类逆转录酶抑制剂（NNRTI）。NNRTIs通过与位于逆转录酶（RT）聚合酶活性位点约10 Å处的变构位点结合来抑制病毒DNA合成中的化学步骤。尽管NNRTIs能有效抑制野生型HIV-1的复制，但结合位点并不保守，且结合口袋中会出现突变。多拉韦林（DOR）是一种处于III期临床试验阶段的新型NNRTI。
我们使用单轮HIV-1感染试验，针对一系列广泛的对NNRTI耐药的突变体测试了RPV和DOR，以确定它们各自的活性。我们还使用分子建模来确定每种化合物的敏感性谱是否与其与RT的结合方式有关。
几个突变体对DOR的敏感性降低。然而，除了E138K之外，我们的数据表明，降低DOR和RPV效力的突变并不重叠。因此，这两种NNRTIs有潜力一起用于联合治疗。我们还表明，DOR和RPV与RT的NNRTI结合口袋结合的位置与它们对NNRTI耐药突变体各自敏感性的差异相关。
这表明（1）DOR对一些众所周知的NNRTI耐药突变敏感，（2）了解NNRTIs与RT的突变敏感性和结合相互作用可用于开发具有非重叠突变敏感性的化合物对。
