用于治疗艾滋病的核苷类似物的毒性及线粒体DNA聚合酶的选择性。
Toxicity of nucleoside analogues used to treat AIDS and the selectivity of the mitochondrial DNA polymerase.
作者信息
Lee Harold, Hanes Jeremiah, Johnson Kenneth A
机构信息
Institute for Cell and Molecular Biology, Department of Chemistry and Biochemistry, University of Texas at Austin, 78712, USA.
出版信息
Biochemistry. 2003 Dec 23;42(50):14711-9. doi: 10.1021/bi035596s.
Incorporation of nucleoside analogues by the mitochondrial DNA polymerase has been implicated as the primary cause underlying many of the toxic side effects of these drugs in HIV therapy. Recent success in reconstituting recombinant human enzyme has afforded a detailed mechanistic analysis of the reactions governing nucleotide selectivity of the polymerase and the proofreading exonuclease. The toxic side effects of nucleoside analogues are correlated with the kinetics of incorporation by the mitochondrial DNA polymerase, varying over 6 orders of magnitude in the sequence zalcitabine (ddC) > didanosine (ddI metabolized to ddA) > stavudine (d4T) >> lamivudine (3TC) > tenofovir (PMPA) > zidovudine (AZT) > abacavir (metabolized to carbovir, CBV). In this review, we summarize our current efforts to examine the mechanistic basis for nucleotide selectivity by the mitochondrial DNA polymerase and its role in mitochondrial toxicity of nucleoside analogues used to treat AIDS and other viral infections. We will also discuss the promise and underlying challenges for the development of new analogues with lower toxicity.
线粒体DNA聚合酶掺入核苷类似物被认为是这些药物在HIV治疗中许多毒副作用的主要潜在原因。重组重组人酶的近期成功使得对控制聚合酶核苷酸选择性和校对核酸外切酶反应的详细机制分析成为可能。核苷类似物的毒副作用与线粒体DNA聚合酶掺入的动力学相关，在齐多夫定（ddC）>去羟肌苷（ddI代谢为ddA）>司他夫定（d4T）>>拉米夫定（3TC）>替诺福韦（PMPA）>齐多夫定（AZT）>阿巴卡韦（代谢为卡波韦，CBV）序列中变化超过6个数量级。在这篇综述中，我们总结了我们目前为研究线粒体DNA聚合酶核苷酸选择性的机制基础及其在用于治疗艾滋病和其他病毒感染的核苷类似物线粒体毒性中的作用所做的努力。我们还将讨论开发低毒性新类似物的前景和潜在挑战。
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