Drug Design Cycle targeting HIV Protease Drug Resistance

该计划的目标是建立一个药物设计周期，旨在开发、测试和 提纯能够限制或消除HIV-1蛋白酶特异性抑制剂的新方法 抗药性。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，连接结构和分子基础 药物相互作用对临床反应的影响。 该方案由四个综合项目和两个配套核心设施组成：1) 计算模型包括HIV-Proteased Rug耐药性的原子细节协同进化， 药物选择压力下的病毒种群动态建模和自动化的应用 学习通知和改进这些模型的方法，并在另一个模型中进行相关的实验工作 项目2)使用有理和组合方法设计和开发下一代缓蚀剂 针对蛋白水解酶和相关的RNA结构的合成技术。3)应用 “点击化学”原位合成方法用于快速开发和进化缓蚀剂 耐药蛋白水解酶；4)研究HIV蛋白水解酶变异性的进展和限度 利用组织培养时程评价、噬菌体展示文库和蛋白酶靶向RNA 适配子选择。5)蛋白质表达和分析核心将提供突变和合成 蛋白水解酶、功能分析、化学探针和抑制物分析。6) 结构和建模核心将提供必要的结构数据和分析，以集成新的 关于蛋白水解酶突变体、蛋白水解酶-抑制物相互作用以及RNA适体-蛋白质的信息 和RNA抑制物的相互作用。 成功的实施和由此产生的知识在治疗中的应用 靶点，将是对药物开发领域的重大贡献，并将在 设计新的、更有效的艾滋病疗法。 ~

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 contributionto this goal will be in the development and application of new chemical,biological and computationalapproaches 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) Computationalmodeling includingatomic detail co-evolution of HIV-proteasedrug resistance, modelingviral populationdynamics under drug selection pressure,and application of automated learningapproaches to inform and refine these models and relatedexperimental work in the other Projects.2) Design and development of next-generation inhibitors using rational and combinatorial synthetictechniques 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) Investigationof the progression and limits of HIV protease variability by exploitingtissue-culturetime-course evaluation, phage display libraries and protease targeted RNA aptamer selection. 5) The Protein Expressionand 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 informationon protease mutants, and protease-inhibitorinteractions, as well as RNA aptamer-protein and RNA-inhibitorinteractions. The successful implementationand the application of the resulting knowledgeto therapeutic targets, would be a major contributionto the field of drug developmentand will be important in the design of new, more efficaciousAIDS therapeutics. ~