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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 HIV-1蛋白水解酶和丙型肝炎病毒NS3蛋白水解酶分别是艾滋病毒和丙型肝炎病毒感染所必需的两种酶。因此，这些酶被认为是治疗这些疾病的抗病毒药物的理想靶点。对于HIV，目前有9种蛋白酶抑制剂可用，几种丙型肝炎病毒NS3蛋白酶抑制剂目前正在进行临床试验。不幸的是，在复制子研究和/或治疗的专利人群中观察到了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，使靶酶保留了裂解病毒底物的能力，但不再能够结合抑制剂。在许多HIV-1蛋白酶变异体中，多个位点突变共同进化，既降低了特定抑制物的亲和力，又增加了酶的活性和适合性。对HIV-1和丙型肝炎病毒NS3蛋白酶与底物和抑制剂的复合体的结晶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HIV-1蛋白水解酶和丙型肝炎病毒NS3蛋白水解酶与底物和抑制剂的复合体的高分辨晶体结构所获得的结构洞察力，将为开发高亲和力抑制剂提供指导，这些抑制剂对这两种病毒系统中新出现的耐药性具有更强的抗药性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.