HIV-1 reverse transcriptase structure: function, inhibition, and resistance

HIV-1逆转录酶结构：功能、抑制和抵抗

基本信息

批准号：
7750025
负责人：
EDWARD ARNOLD
金额：
$ 76.48万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-02-01 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7750025
关键词：
Acquired Immunodeficiency Syndrome Active Sites Anti-HIV Agents Antiviral Agents Binding Binding Sites Biochemical Biological Catalysis Characteristics Chemicals Chemistry Clinical Collaborations Commit Complex Crystallization Crystallography DNA Data Deposition Development Diphosphates Drug Delivery Systems Drug Design Drug resistance Engineering Enzymes Excision Fingers Foscarnet Funding Generations Grant HIV HIV-1 Reverse Transcriptase Human Resources Imagery Knowledge Laboratories Learning Ligands Methodology Methods Molecular Multi-Drug Resistance Mutation NNRTI-resistance Nucleic Acids Nucleosides Nucleotides Patients Pharmaceutical Preparations Polymerase Production Property Proteins Publications RNA RNA-Directed DNA Polymerase Reaction Reagent Research Personnel Resistance Resolution Retroviridae Reverse Transcriptase Inhibitors Ribonuclease H Screening procedure Site Specificity Staging Structure Technology Transfer RNA United States National Institutes of Health Universities Variant Viral Physiology Work X ray diffraction analysis X-Ray Crystallography X-Ray Diffraction Zidovudine resistance analog base chemical synthesis computer studies crosslink design drug resistant virus improved inhibitor/antagonist iterative design multidrug resistance inhibition therapy mutant non-nucleoside reverse transcriptase inhibitors novel public health relevance resistance mutation success

项目摘要

DESCRIPTION (provided by applicant): HIV-1 reverse transcriptase (RT) is a central target for antiviral treatment of AIDS and detailed knowledge of its structure and function has important clinical and biological consequences. Both nucleoside and non-nucleoside RT inhibitors are used as effective drugs for treating AIDS, but success can be limited by the emergence of drug-resistant viral variants. Novel non-nucleoside RT inhibitors have been developed through structure-based methods, including the recently approved drug etravirine/TMC125/Intelence, and we propose to carry out crystallographic studies that could enable structure-guided improvement of additional classes of RT inhibitors. The proposed work will involve structure determination of wild-type and drug-resistant HIV-1 RT in the presence and absence of nucleic acid substrates and inhibitors. Structural studies of inhibitor will explore binding sites for known drugs (NRTIs and NNRTIs) as well as other potential drug targeting sites including the RNase H active site. Use of strategically modified protein and nucleic acids will enhance the efficiency and quality of the structural studies. The structures determined will enhance our understanding of mechanisms of polymerase and RNase H catalysis, inhibition, and of drug resistance. PUBLIC HEALTH RELEVANCE: HIV-1 reverse transcriptase (RT) is a central target for antiviral treatment of AIDS and detailed knowledge of its structure and function has important clinical and biological consequences. Both nucleoside and non-nucleoside RT inhibitors are used as effective drugs for treating AIDS, but success can be limited by the emergence of drug-resistant viral variants. The proposed studies will enhance opportunities for targeting known and new sites on RT including RNase H, the only HIV enzyme not yet blocked by anti-AIDS drugs.

描述（由申请人提供）：HIV-1逆转录酶（RT）是艾滋病抗病毒治疗的核心靶点，对其结构和功能的详细了解具有重要的临床和生物学意义。核苷和非核苷RT抑制剂均被用作治疗艾滋病的有效药物，但成功可能会因耐药病毒变种的出现而受到限制。新型非核苷类逆转录酶抑制剂已经通过基于结构的方法开发出来，包括最近批准的药物依曲韦林/TMC125/Intelence，我们建议进行晶体学研究，以实现结构指导下改进其他类别的逆转录酶抑制剂。拟议的工作将涉及在存在和不存在核酸底物和抑制剂的情况下野生型和耐药 HIV-1 RT 的结构测定。抑制剂的结构研究将探索已知药物（NRTI 和 NNRTI）的结合位点以及其他潜在的药物靶向位点，包括 RNase H 活性位点。使用策略性修饰的蛋白质和核酸将提高结构研究的效率和质量。确定的结构将增强我们对聚合酶和 RNase H 催化、抑制和耐药机制的理解。公共卫生相关性：HIV-1 逆转录酶 (RT) 是艾滋病抗病毒治疗的核心靶点，详细了解其结构和功能具有重要的临床和生物学意义。核苷和非核苷RT抑制剂都被用作治疗艾滋病的有效药物，但成功可能会因耐药病毒变种的出现而受到限制。拟议的研究将增加针对 RT 上已知和新位点的机会，包括 RNase H，这是唯一尚未被抗艾滋病药物阻断的 HIV 酶。