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）：我们建议研究艾滋病毒蛋白酶抑制背景下耐药性的发展，以开发和测试针对该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机制，从而能够建模和设计更可持续的抗病毒治疗策略。该计划由四个高度集成的项目和三个配套核心设施组成：项目 1，将通过开发和应用药物/靶标相互作用的详细原子模型、对病毒群体动态和患者反应进行建模，增强和扩展耐药性的计算共同进化方法在药物选择压力下，利用自动学习和隐马尔可夫建模方法来通知和完善这些模型；项目 2 将利用高通量晶体学的能力，使用片段库来寻找和表征蛋白质靶标上的新结合位点，以帮助构建新的抑制剂先导化合物，以保持针对多位点 PR 突变体的功效，并与项目 1 和 1 中的优化和合成工作相结合。分别为3个；项目3将利用他们的“点击化学”合成方法，与项目1和2结合快速开发和进化基于片段的新型抑制剂，并与项目4一起开发耐药探针；项目 4 将实验性地描述 PR 内和 Gag-Pol 其余部分中 HIV 抗性响应蛋白酶抑制的演变，方法是利用组织培养时程评估传代病毒在已识别的抑制剂存在下以及从深部对选定的患者样本进行基因分析；核心A将为该计划提供突变型和野生型蛋白酶、功能测定和化学探针以及抑制剂分析； Core 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体和蛋白酶抑制剂相互作用的新信息； Core C 将收集并向项目 1 和 4 提供 HIV 感染患者的时程抗逆转录病毒治疗数据以及高度耐药个体的血液样本，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接受药物治疗，使他们过上富有成效的生活，但病毒可以通过对这些药物产生耐药性来破坏这种治疗。这项研究旨在详细了解艾滋病毒耐药性，目标是开发新的治疗策略，以实现更可持续的治疗来预防艾滋病。