The High Genetic Barrier of EFdA/MK-8591 Stems from Strong Interactions with the Active Site of Drug-Resistant HIV-1 Reverse Transcriptase.
The High Genetic Barrier of EFdA/MK-8591 Stems from Strong Interactions with the Active Site of Drug-Resistant HIV-1 Reverse Transcriptase.
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DOI：
10.1016/j.chembiol.2018.07.014
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发表时间：
2018-10-18
影响因子：
8.6
通讯作者：
Maeda K
中科院分区：
文献类型：
--
作者：
Takamatsu Y;Das D;Kohgo S;Hayashi H;Delino NS;Sarafianos SG;Mitsuya H;Maeda K
4′-乙炔基-2-氟-2 ′-脱氧腺苷（EFdA/MK-8591）是一种核苷类逆转录酶抑制剂（NRTI），是一种有效的长效抗人类免疫缺陷病毒1型（HIV-1）药物。EFdA及其衍生物具有修饰的4′-部分，并有效抑制对现有NRTI耐药的广谱HIV-1毒株的复制。在这里，我们报告了EFdA和具有4′-乙炔基或4′-氰基部分的NRTI对具有M184 V突变的HIV-1和多种NRTI耐药的HIV-1发挥活性，而具有其他部分的NRTI（例如，4′-甲基）没有表现出这种活性。结构分析表明，EFdA和4′-乙炔基-NRTI（而不是其他4′-修饰的NRTI）与逆转录酶的关键氨基酸残基形成强的货车范德华相互作用。这种相互作用即使在广泛的耐药性赋予M184 V取代的存在下也能保持，从而有效地抑制耐药HIV-1菌株。这些发现也解释了EFdA效力的机制，并为进一步设计抗HIV-1治疗药物提供了见解。EFdA对多重耐药HIV-1病毒株具有有效的抗病毒活性，目前正在进行临床试验。Takamatsu等评价了EFdA衍生物的抗病毒活性和结构分析，并报告4′-乙炔基或4′-氰基部分是对耐药HIV-1毒株具有强效抗病毒活性的关键结构特征。
4′-Ethynyl-2-fluoro-2′-deoxyadenosine (EFdA/MK-8591), a nucleoside reverse transcriptase inhibitor (NRTI) under clinical trials, is a potent and promising long-acting anti-human immunodeficiency virus type 1 (HIV-1) agent. EFdA and its derivatives possess a modified 4′-moiety and potently inhibit the replication of a wide spectrum of HIV-1 strains resistant to existing NRTIs. Here, we report that EFdA and NRTIs with a 4′-ethynyl- or 4′-cyano-moiety exerted activity against HIV-1 with an M184V mutation and multiple NRTI-resistant HIV-1s, whereas NRTIs with other moieties (e.g., 4′-methyl) did not show this activity. Structural analysis indicated that EFdA and 4′-ethynyl-NRTIs (but not other 4′-modified NRTIs), formed strong van der Waals interactions with critical amino acid residues of reverse transcriptase. Such interactions were maintained even in the presence of a broad resistance-endowing M184V substitution, thus potently inhibiting drug-resistant HIV-1 strains. These findings also explain the mechanism for the potency of EFdA and provide insights for further design of anti-HIV-1 therapeutics. EFdA exerts potent antiviral activity against multiple-drug-resistant HIV-1 strains and is now undergoing clinical trials. Takamatsu et al. evaluated the antiviral activity and structural analysis of EFdA derivatives and report that 4′-ethynyl or 4′-cyano moiety are the key structural features for the potent antiviral activity against drug-resistant HIV-1 strains.
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影响因子：
4.9
作者：
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影响因子：
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Mitsuya, Hiroaki
影响因子：
4.9
作者：
Kodama, EI;Kohgo, S;Mitsuya, H
通讯作者：
Mitsuya, H