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

HIV-1逆转录酶结构：功能、抑制和抵抗

• 批准号: 8416384
• 负责人: EDWARD ARNOLD
• 金额: $ 67.66万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 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/8416384
• 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 Design; Drug Targeting; Drug resistance; Engineering; Enzymes; Excision; Fingers; Foscarnet; Funding; Generations; Grant; HIV; HIV-1; 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; 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; screening; success

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.

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。