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 改进能够限制或消除HIV-1蛋白酶的特异性抑制剂的新方法 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，连接结构和分子基础， 药物相互作用与临床反应。 该计划包括四个综合项目和两个配套核心设施： 计算建模包括HIV蛋白酶耐药性的原子细节共同进化， 药物选择压力下的病毒种群动力学建模，以及自动 学习方法，以通知和完善这些模型和相关的实验工作，在其他 项目2）利用合理的和组合的方法设计和开发下一代抑制剂 针对蛋白酶和相关RNA结构的合成技术。3)的应用 "点击化学"原位合成方法用于快速开发和发展抑制剂， 耐药蛋白酶; 4）研究HIV蛋白酶变异的进展和限制， 利用组织培养时程评价、噬菌体展示文库和蛋白酶靶向RNA 适体选择。5)蛋白质表达和分析核心将提供突变和合成 蛋白酶、功能测定、化学探针和抑制剂分析。6)的 结构和建模核心将提供必要的结构数据和分析，以整合新的 关于蛋白酶突变体、蛋白酶-底物相互作用以及RNA适体-蛋白质的信息 和RNA-底物相互作用。 成功的实施和应用所产生的知识，以治疗 目标，将是对药物开发领域的重大贡献， design设计of new新，more efficaciousAIDS有效therapeutic治疗. ~

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. ~