Resistance Driven Structural Design for HIV Therapies

HIV 疗法的阻力驱动结构设计

• 批准号: 7931497
• 负责人: ARTHUR J. OLSON
• 金额: $ 40.1万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7931497
• 关键词: Acquired Immunodeficiency Syndrome; Anti-Retroviral Agents; Binding Sites; Bioinformatics; Biological Assay; Blood specimen; Chemicals; Computer Analysis; Core Facility; Crystallography; Data; Development; Drug Delivery Systems; Drug resistance; Evaluation; Evolution; Gagging; Genomics; Goals; HIV; HIV Protease; HIV drug resistance; HIV therapy; Individual; Learning; Libraries; Life; Link; Modeling; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Population Dynamics; Protease Inhibitor; Proteins; Resistance; Resistance development; Rest; Sampling; Site; Synthesis Chemistry; Testing; Therapeutic; Time; Viral; Virus; base; design; genetic analysis; inhibitor/antagonist; markov model; model design; mutant; novel; novel therapeutics; pandemic disease; pressure; prevent; programs; response; tissue culture; viral resistance

DESCRIPTION (provided by applicant): We propose to study the development of drug resistance in the context of HIV protease inhibition to develop and test structural and synthetic strategies in response to this mechanism. The overall goal of this Program Project is to understand the mechanisms of viral resistance, enabling modeling and design of more sustainable anti-viral therapeutic strategies. The Program consist of four highly integrated Projects and three supporting Core facilities: Project 1, will enhance and extend a computational co-evolution approach to drug resistance by developing and applying detailed atomic models of drug/target interactions, modeling viral population dynamics and patient response under drug selection pressure, exploiting automated learning and hidden Markov modeling approaches to inform and refine these models; Project 2 will exploit the capabilities of high throughput crystallography to find and characterize novel binding sites on the protein target using fragment libraries to help construct new inhibitor leads to maintain efficacy against multi-site PR mutants, linking with optimization and synthetic efforts in Projects 1 and 3 respectively; Project 3 will utilize their "Click Chemistry" synthetic approaches for rapid development and evolution of novel fragment-based inhibitors in conjunction with Projects 1 and 2, and develop resistance probes with Project 4; Project 4 will experimentally characterize the evolution of HIV resistance in response to protease inhibition both within PR and in the rest of Gag-Pol, by exploiting tissue-culture time-course evaluation passaged virus in the presence of identified inhibitors, as well as from deep genetic analysis of selected patient samples; Core A will provide mutant and wildtype proteases, functional assays and chemical probes, and inhibitor analyses for the Program; Core B will provide the necessary x-ray structural data and computational analysis to integrate new information on protease mutants, and protease-inhibitor interactions; and Core C will assemble and make available to projects 1 and 4 time-course anti-retroviral treatment data on HIV infected patients as well as blood samples from highly resistant individuals for in-depth bioinformatic and viral genomic analyses. AIDS remains the major pandemic of our time. While patients infected with HIV can now be treated with drugs that enable them to live productive lives, the virus can subvert this treatment by developing resistance to these drugs. This study is aimed at a detailed understanding of HIV drug resistance, with the goal of developing new therapeutic strategies for more sustainable treatments to prevent AIDS.

描述(由申请人提供)：我们建议在HIV蛋白酶抑制的背景下研究耐药性的发展，以开发和测试针对这一机制的结构和合成策略。该计划项目的总体目标是了解病毒耐药性的机制，使建模和设计更可持续的抗病毒治疗策略成为可能。该计划由四个高度集成的项目和三个辅助核心设施组成：项目1将通过开发和应用药物/靶相互作用的详细原子模型、模拟病毒种群动态和患者在药物选择压力下的反应、利用自动学习和隐马尔可夫建模方法来告知和改进这些模型，来增强和扩展计算协同进化方法；项目2将利用高通量结晶学的能力来寻找和表征蛋白质靶标上的新结合位点，使用片段文库来帮助构建新的抑制物领导保持对多位点PR突变的有效性，分别与项目1和3中的优化和合成工作相联系；项目3将结合项目1和项目2，利用他们的“点击化学”合成方法，快速开发和进化新的基于片段的抑制剂，并与项目4一起开发耐药性探针；项目4将通过在存在已确定抑制剂的情况下利用组织培养时程评估传代病毒，以及从选定的患者样本的深入遗传分析，来实验地表征在PR和GAG-Pol的其余部分中响应蛋白酶抑制的艾滋病毒耐药性的演变；核心A将为该计划提供突变和野生型蛋白酶、功能分析和化学探针，以及抑制剂分析；核心B将提供必要的X射线结构数据和计算分析，以整合有关蛋白酶突变和蛋白酶-抑制物相互作用的新信息；核心C将汇编并向项目1和4提供艾滋病毒感染患者的时程抗逆转录病毒治疗数据以及高耐药性个人的血液样本，以进行深入的生物信息学和病毒基因组分析。艾滋病仍然是我们这个时代的主要流行病。虽然感染艾滋病毒的患者现在可以通过药物进行治疗，使他们能够过上富有成效的生活，但病毒可以通过对这些药物产生抗药性来颠覆这种治疗。这项研究旨在详细了解艾滋病毒耐药性，目的是开发新的治疗策略，以更可持续的治疗来预防艾滋病。