Mechanism of interaction of humanmitochondrial DNA polymerase γ withthe novel nucleoside reversetranscriptase inhibitor 4'-ethynyl-2-fluoro-2'-deoxyadenosine indicates alow potential for host toxicity
Mechanism of interaction of humanmitochondrial DNA polymerase γ withthe novel nucleoside reversetranscriptase inhibitor 4'-ethynyl-2-fluoro-2'-deoxyadenosine indicates alow potential for host toxicity
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人线粒体 DNA 聚合酶 γ 与新型核苷逆转录酶抑制剂 4-乙炔基-2-氟-2-脱氧腺苷的相互作用机制表明对宿主毒性的可能性较低
DOI：
10.1128/aac.05729-11
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
K.S
中科院分区：
文献类型：
--
作者：
Sohl;C.D.;Singh;K.;Kasiviswanathan,R.;Copeland;W.C.;Mitsuya;H.,Sarafianos;S.G.;Anderson;K.S
有效的抗逆转录病毒药物4 ' -乙基-2-氟-2 ' -脱氧腺苷（EFdA）是治疗HIV感染的一种很有前途的实验药物。采用预稳态动力学表征EFdA-triphosphate （EFdA-TP）与人线粒体DNA聚合酶γ (Pol γ)的相互作用，以评估其潜在毒性。Pol γ结合EFdA-TP的效率比dATP低4300倍，切除率与ddATP相似。这强烈表明EFdA是一个较差的Pol γ底物，表明Pol γ介导的毒性很小，尽管这需要在临床环境下进行检查。
The potent antiretroviral 4′-ethynyl-2-fluoro-2′-deoxyadenosine (EFdA) is a promising experimental agent for treating HIV infection. Pre-steady-state kinetics were used to characterize the interaction of EFdA-triphosphate (EFdA-TP) with human mitochondrial DNA polymerase γ (Pol γ) to assess the potential for toxicity. Pol γ incorporated EFdA-TP 4,300-fold less efficiently than dATP, with an excision rate similar to ddATP. This strongly indicates EFdA is a poor Pol γ substrate, suggesting minimal Pol γ-mediated toxicity, although this should be examined under clinical settings.