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Structural Basis for Antiviral Drug Mitochondrial Toxicity

抗病毒药物线粒体毒性的结构基础

基本信息

批准号：
10356145
负责人：
Yuhui Yin
金额：
$ 39.12万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10356145
关键词：
Acquired Immunodeficiency Syndrome Active Sites Adverse reactions Affect Affinity Antiviral Agents Apoptosis Bypass Cell Cycle Cell Death Cells Chemical Structure Chemicals Clinical Trials Complex Coupled Cross Reactions Crystallization DNA DNA Primase DNA biosynthesis DNA-Directed DNA Polymerase DNA-Directed RNA Polymerase Data Discrimination Drug Design Drug Interactions Drug Targeting Drug toxicity Energy Supply Excision Exonuclease FDA approved Genetic Transcription Goals Grant HIV HIV/HCV Hepatitis C Hepatitis C co-infection Hepatitis C virus Human Individual Infection Investigation Lamivudine Mediating Methods Mitochondria Mitochondrial DNA Mitochondrial RNA Molecular Natural Immunity Natural Selections Nucleosides Nucleotides Patients Persons Pharmaceutical Preparations Phase Polymerase Population Protein Biosynthesis Proteins Public Health Purine Nucleotides Purines Pyrimidine RNA RNA chemical synthesis Reaction Reagent Regimen Research Resolution Reverse Transcriptase Inhibitors Ribonucleosides Ribonucleotides Site Stavudine Structure Therapeutic Toxic effect Toxicity Tests Transcription Elongation Transcription Initiation Viral Zalcitabine Zidovudine abacavir analog antiretroviral therapy base co-infection combat design drug structure emtricitabine enantiomer human DNA inhibitor inhibitor therapy insight mitochondrial dysfunction nucleoside analog public health relevance rational design replicase response success transmission process

项目摘要

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.

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。