Drug Design Cycle Targeting HIV Protease Drug Resistance

描述(由申请人提供)：该计划的目标是建立一个药物设计周期，旨在开发、测试和改进能够限制或消除耐药性的HIV-1蛋白酶特定抑制剂的新方法。我们对这一目标的贡献将是开发和应用新的化学、生物和计算方法，将药物相互作用的结构和分子基础与临床反应联系起来。该计划由四个综合项目和两个辅助核心设施组成：1)计算建模，包括艾滋病毒-蛋白酶耐药性的原子细节共同进化，建模药物选择压力下的病毒种群动态，以及应用自动学习方法来告知和完善这些模型以及其他项目中的相关实验工作。2)设计和开发下一代的抑制剂，使用合理的和组合的合成技术，同时针对蛋白酶和相关的RNA结构。3)应用“点击化学”原位合成方法快速开发和进化耐药蛋白酶的抑制剂；4)通过组织培养时程评估、噬菌体展示文库和蛋白酶靶向RNA适配子选择来研究HIV蛋白酶变异性的进展和限制。5)蛋白质表达和分析核心将提供突变和合成蛋白酶、功能分析、化学探针和 对该计划的抑制分析。6)结构和建模核心将提供必要的结构数据和分析，以整合有关蛋白酶突变、蛋白酶-抑制剂相互作用以及RNA适体-蛋白质和RNA-抑制剂相互作用的新信息。成功地将所获得的知识应用于治疗目标，将是对药物开发领域的重大贡献，并将在设计新的、更有效的艾滋病治疗方法方面发挥重要作用。

DESCRIPTION (provided by applicant): The goal of this Program is to establish a drug design cycle aimed at developing, testing and refining novel approaches to specific inhibitors of HIV-1 protease capable of limiting or eliminating drug resistance. Our contribution to this goal will be in the development and application of new chemical, biological and computational approaches that connect the structural and molecular basis of drug interaction to the clinical response. The program consists of four integrated Projects and two supporting Core facilities: 1) Computational modeling including atomic detail co-evolution of HIV-protease drug resistance, modeling viral population dynamics under drug selection pressure, and application of automated learning approaches to inform and refine these models and related experimental work in the other Projects. 2) Design and development of nextgeneration inhibitors using rational and combinatorial synthetic techniques targeting both the protease and associated RNA structures. 3) Application of "Click Chemistry" in situ synthetic approaches for rapid development and evolution of inhibitors to drug resistant proteases; 4) Investigation of the progression and limits of HIV protease variability by exploiting tissue-culture time-course evaluation, phage display libraries and protease targeted RNA aptamer selection. 5) The Protein Expression and Analysis Core will provide mutant and synthetic proteases, functional assays, chemical probes, and inhibitor analyses for the Program. 6) The Structure and Modeling Core will provide the necessary structural data and analysis to integrate new information on protease mutants, and protease-inhibitor interactions, as well as RNA aptamer-protein and RNA-inhibitor interactions. The successful implementation and the application of the resulting knowledge to therapeutic targets, would be a major contribution to the field of drug development and will be important in the design of new, more efficacious AIDS therapeutics.