STRUCTURAL STUDIES OF VIRAL PROTEASES: HIV-1 PROTEASE AND HCV NS3 PROTEASE

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 HIV-1蛋白酶和HCV NS 3蛋白酶分别是HIV和HCV感染所必需的两种酶。 因此，这些酶被认为是用于治疗这些疾病的抗病毒药物的理想靶标。 对于HIV，目前有9种蛋白酶抑制剂可用，并且几种HCV NS 3蛋白酶抑制剂目前处于临床试验中。 不幸的是，在复制子研究和/或治疗的患者群体中观察到对大多数这些抑制剂的耐药性。 我们的实验室将耐药性视为分子识别的变化，使得靶酶保留切割病毒底物的能力，但不再能够结合抑制剂。 在许多HIV-1蛋白酶变体中，多位点突变共同进化以降低特定抑制剂的亲和力并增加酶的活力和适应性。HIV-1蛋白酶和HCV NS 3蛋白酶与底物和抑制剂的复合物的晶体学研究将被证明是有价值的，以确定介导底物识别的分子相互作用，同时降低对特定抑制剂的亲和力。通过分析与底物和抑制剂复合的HIV-1蛋白酶和HCV NS 3蛋白酶的高分辨率晶体结构获得的结构见解将作为开发高亲和力抑制剂的指导，这些抑制剂对两种病毒系统中出现的耐药性更加稳健。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. HIV-1 protease and HCV NS3 protease are both enzymes that are required for HIV and HCV infection respectably. Therefore these enzymes are considered ideal targets for anti-viral drugs for the treatment of these diseases. For HIV there are currently 9 protease inhibitors available and several HCV NS3 protease inhibitors are currently in clinical trials. Unfortunately drug-resistance to most of these inhibitors has been observed in replicon studies and/or treated patent populations. Our lab views drug-resistance as a change in molecular recognition such that the target enzyme retains the ability to cleave viral substrates but is no longer able to bind inhibitor. In many HIV-1 protease variants multiple site mutations co-evolve to both decrease the affinity of a particular inhibitor and increase the viability and fitness of the enzyme. Crystallographic studies of HIV-1 protease and HCV NS3 protease in complex with substrates and inhibitors will prove to be valuable in order to determine molecular interactions that mediate substrate recognition while decreasing affinity to a particular inhibitor. Structural insights gained by analyzing high resolution crystal structures of HIV-1 protease and HCV NS3 protease in complex with substrates and inhibitors will serve as a guide to develop high affinity inhibitors that are more robust against emerging drug resistant in both viral systems.