Activity of Resistant Variants of HIV Protease

描述(申请人提供)：HIV-1蛋白酶是病毒复制所必需的，为抗病毒药物治疗艾滋病患者提供了一个非常有效的靶点。然而，目前抗病毒蛋白水解酶抑制剂的长期有效性受到耐药蛋白水解酶突变体快速发展的限制。为了开发新的抑制剂和新的治疗策略，有必要了解HIV蛋白酶及其耐药突变体的作用的分子基础。晶体结构和底物专一性的分析已经被用来确定重要的抑制剂-蛋白酶相互作用和对底物识别至关重要的蛋白酶残基。这些关键残基预计会出现在HIV蛋白酶的耐药变体中，并且是已知耐药变体中最常见的突变残基之一。对在耐药分离株中发现的HIV-1蛋白酶突变体的结构和活性进行了表征。PI小组的分析表明，抗药性突变体改变了代表多蛋白加工关键步骤的多肽的催化活性和特异性，并改变了二聚体的稳定性。所有这些效应预计将有助于在存在蛋白酶抑制剂的情况下增加病毒复制。 已经发展了计算方法来预测HIV蛋白酶多肽底物的相对裂解效率和蛋白酶突变体的相对抑制。将对临床抑制剂进行比较，以确定对改善对耐药蛋白酶变异体的抑制至关重要的因素。基于结构的设计将有助于开发新的蛋白酶抑制剂，作为克服耐药性的下一代抗病毒药物。

DESCRIPTION (provided by applicant): The HIV-1 protease is essential for viral replication and has provided a very effective target for antiviral drugs to treat AIDS patients. However, the long-term effectiveness of current antiviral protease inhibitors is limited by the rapid development of resistant protease mutants. It is necessary to understand the molecular basis for the action of HIV protease and its inhibitor-resistant mutants in order to develop new inhibitors and new therapeutic strategies. Analysis of crystal structures and substrate specificity has been used to identify important inhibitor-protease interactions and the protease residues that are critical for recognition of substrates. These key residues were predicted to occur in the inhibitor resistant variants of HIV protease and are among the most commonly mutated residues in the known resistant variants. The structures and activities of HIV-1 protease mutants found in resistant isolates have been characterized. Analyses by the PI's group have demonstrated that resistant mutants have altered catalytic activity and specificity for the cleavage of peptides representing critical steps in polyprotein processing, and altered dimer stability. All these effects are expected to contribute to increased viral replication in the presence of protease inhibitors. Computational methods have been developed to predict the relative efficiency of cleavage of peptide substrates of HIV protease, and relative inhibition of protease mutants. Clinical inhibitors will be compared to define the factors important for improved inhibition of resistant protease variants. Structure-based designs will assist with development of new protease inhibitors as the next generation of antiviral agents to overcome resistance.