Rilpivirine and Doravirine Have Complementary Efficacies Against NNRTI-Resistant HIV-1 Mutants.
Rilpivirine and Doravirine Have Complementary Efficacies Against NNRTI-Resistant HIV-1 Mutants.
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DOI：
10.1097/qai.0000000000001031
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发表时间：
2016-08-15
期刊：
影响因子：
--
通讯作者：
Hughes SH
中科院分区：
文献类型：
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作者：
Smith SJ;Pauly GT;Akram A;Melody K;Ambrose Z;Schneider JP;Hughes SH
利匹韦林 (RPV) 是 FDA 批准用于对抗 HIV-1 感染的最新非核苷逆转录酶抑制剂 (NNRTI)。 NNRTI 通过与距离逆转录酶 (RT) 聚合酶活性位点约 10 Å 的变构位点结合来抑制病毒 DNA 合成中的化学步骤。尽管 NNRTI 有效抑制 WT HIV-1 的复制，但结合位点并不保守，并且结合口袋中会出现突变。 Doravirine (DOR) 是一种新的 NNRTI，处于 III 期临床试验中。使用单轮 HIV-1 感染测定，我们针对大量 NNRTI 抗性突变体测试了 RPV 和 DOR，以确定它们各自的活性。我们还使用分子模型来确定每种化合物的敏感性特征是否与其结合 RT 的方式相关。一些突变体表现出对 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 效力的突变是不重叠的。因此，这两种 NNRTI 有可能在联合治疗中一起使用。我们还表明，DOR 和 RPV 与 RT 的 NNRTI 结合袋结合的位置与它们各自对 NNRTI 抗性突变组的易感性差异相关。这表明 (1) DOR 对许多众所周知的 NNRTI 抗性突变敏感，并且 (2) 对突变敏感性以及 NNRTI 与 RT 的结合相互作用的了解可用于开发具有非重叠突变敏感性的化合物对。
Rilpivirine (RPV) is the latest non-nucleoside reverse transcriptase inhibitor (NNRTI) to be FDA-approved 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 WT HIV-1, the binding site is not conserved, and mutations arise in the binding pocket. Doravirine (DOR) is a new a 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 two 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.