4'-Ethynyl-2-fluoro-2'-deoxyadenosine, MK-8591: a novel HIV-1 reverse transcriptase translocation inhibitor.
4'-Ethynyl-2-fluoro-2'-deoxyadenosine, MK-8591: a novel HIV-1 reverse transcriptase translocation inhibitor.
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DOI：
10.1097/coh.0000000000000467
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发表时间：
2018-07
影响因子：
4.1
通讯作者：
Sarafianos SG
中科院分区：
文献类型：
--
作者：
Markowitz M;Sarafianos SG
4‘-乙炔基-2-氟-2’-脱氧腺苷(EFdA)是逆转录酶(NRTI)的核苷抑制剂，具有新的作用机制、独特的结构和无与伦比的抗HIV-1活性。我们将对其结构和功能、抗病毒活性、耐药谱以及作为抗逆转录病毒用于HIV-1感染的治疗和暴露前预防(PrEP)的潜力进行综述。EFdA对野生型(EC50低至50 PM)和大多数高度抵抗NRTI的病毒具有活性。活性代谢物EFdA-三磷酸(TP)在人和恒河猴血细胞中有较长的细胞内半衰期。结果，在感染SIVmac251的恒河猴和感染HIV-1的个体身上测试的单一药物剂量显示出持续7至10天的强大抗病毒活性。EFdA作为PrEP在恒河猴/SIV低剂量直肠内激发模型中的临床前研究表明，在临床相关剂量下给予EFdA完全保护作用。EFdA是一种新型的抗逆转录病毒药物，对野生型病毒和NRTI耐药病毒都有活性。由于其活性部分的细胞内半衰期延长，它可以灵活地至少每天到每周或更长时间地给药。
4′-ethynyl-2-fluoro-2′-deoxyadenosine (EFdA) is a nucleoside inhibitor of reverse transcriptase (NRTI) with a novel mechanism of action, unique structure, and amongst NRTIs, unparalleled anti-HIV-1 activity. We will summarize its structure and function, antiviral activity, resistance profile, and potential as an antiretroviral for use in the treatment and pre-exposure prophylaxis (PrEP) of HIV-1 infection. EFdA is active against wild type (EC50 as low as 50 pM) and most highly NRTI resistant viruses. The active metabolite, EFdA-triphosphate (TP), has been shown to have a prolonged intracellular half-life in human and rhesus blood cells. As a result, single drug doses tested in SIVmac251-infected rhesus macaques and HIV-1-infected individuals exhibited robust antiviral activity of 7 to 10 days duration. Preclinical studies of EFdA as PrEP in the rhesus macaque/SHIV low-dose intrarectal challenge model has shown complete protection when given in clinically relevant doses. EFdA is a novel antiretroviral with activity against both wild type and NRTI-resistant viruses. As a result of the prolonged intracellular half-life of its active moiety, it is amenable to flexibility in dosing of at least daily to weekly and perhaps longer.