UNDERSTANDING DRUG RESISTANCE MECHANISMS OF HIV-1 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蛋白酶是治疗HIV-1感染的最有效的抗病毒药物的靶点。所有这些药物都是基于结构的药物设计的结果。该酶是药物治疗的理想靶点，因为它在10个或更多个独特的非同源位点处理Gag和GagPol多蛋白，这些位点对病毒粒子的成熟和病毒的传播至关重要。不幸的是，在药物治疗的选择压力下，许多存活的、具有抗药性的HIV-1蛋白酶变体已经进化出来。分子水平上的耐药性是酶对结合抑制剂的相对亲和力与其结合和切割底物的能力之间识别事件平衡的微妙变化。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蛋白酶与底物和抑制剂形成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，这些抑制剂对新出现的耐药HIV-1变异株更具抵抗力。

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 is the target of the most potent anti-viral drugs for the treatment of HIV-1 infection. All of these drugs are the consequence of structure-based drug design. The protease is an ideal target for drug therapy since it processes the Gag and GagPol polyproteins in ten or more unique non-homologous sites that are critical for virion maturation and thus the spread of the virus. Unfortunately, many viable, drug resistant variants of HIV-1 protease have evolved under the selective pressure of drug therapy. Drug resistance at the molecular level is a subtle change in the balance of recognition events between the relative affinity of the enzyme to bind inhibitors and its ability to bind and cleave substrates. 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 on HIV-1 protease in complex with substrates and inhibitors will prove to be valuable in order to determine molecular interactions that mediate substrate recognition whilst decreasing affinity to a particular inhibitor. Structural insights gained by analyzing high resolution crystal structures of HIV-1 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 HIV-1 variants.