Structural Basis for Antiviral Drug Mitochondrial Toxicity

摘要 HIV和HCV的合并感染是一个主要的公共卫生威胁，需要综合治疗方案。的 抗逆转录病毒疗法（ART）的基石是核苷类似物抑制剂、核苷逆转录酶抑制剂、核苷类似物抑制剂、核苷类似物抑制 针对HIV的转录酶抑制剂（NRTI）和针对HCV的核糖核苷类似物抑制剂（RAI）。尽管 在几个成功的案例中，许多具有相似化学结构的化合物在临床试验中失败， 药物毒性研究表明，NRTI的毒性是由线粒体DNA聚合酶介导的， Pol g和RAIs与线粒体RNA聚合酶（hmtRNAP）交叉反应，引起线粒体RNA聚合酶（hmtRNAP）的表达。 功能障碍线粒体对细胞活动至关重要;它们为细胞提供能量，调节细胞周期， 通过细胞凋亡导致细胞死亡并参与先天免疫。我们的中心假设是， 人线粒体聚合酶是抗病毒药物毒性的主要原因。我们的长期目标是 研究是为了了解和克服线粒体药物毒性。我们建议揭示结构和 核苷类抗病毒药物线粒体毒性的分子机制 与人类DNA和RNA聚合酶的相互作用。我们的具体目标包括：（1）揭示结构 Polg对NRTI的双管齐下的防御的基础和2）提供hmtRNAP介导的机制 RAIs药物毒性。拟议的研究将为线粒体聚合酶提供全面的观点 介导的抗病毒药物毒性，并提供低毒性抗病毒试剂设计的见解。

ABSTRACT Coinfection of HIV and HCV is a major public health threat and requires integrated therapeutic regimens. The cornerstones of antiretroviral therapy (ART) are nucleoside analogue inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs) against HIV and ribonucleoside analog inhibitors (RAIs) against HCV. Despite several success cases, many compounds with similar chemical structures failed during clinical trials due to drug toxicity. Investigations have revealed that NRTIs' toxicity is mediated by mitochondrial DNA polymerase, Pol g, and RAIs cross-react with mitochondrial RNA polymerase (hmtRNAP), causing mitochondrial dysfunction. Mitochondria are vital to cellular activities; they supply energy to the cell, regulate cell cycle and cell death through apoptosis and participate in innate immunity. Our central hypothesis is that inhibition of human mitochondrial polymerases is a major cause of antiviral drug toxicity. The long-term goal of our research is to understand and overcome mitochondrial drug toxicity. We propose to reveal the structural and molecular mechanism for nucleoside-based antiviral drug mitochondrial toxicity by studying antiviral drug interactions with both human DNA and RNA polymerases. Our specific aims include 1) to reveal structural basis for Pol g's two-pronged defense against NRTIs and 2) to provide a mechanism for hmtRNAP mediated RAIs drug toxicity. The proposed studies will offer a comprehensive view for mitochondrial polymerases mediated antiviral drug toxicity, and provide insight in design of low-toxic antiviral reagents.