Activity of Resistant Variants of HIV Protease

描述（由申请人提供）：HIV-1蛋白酶是病毒复制所必需的，并为治疗艾滋病患者的抗病毒药物提供了非常有效的靶点。然而，目前抗病毒蛋白酶抑制剂的长期有效性受到耐药蛋白酶突变体的快速发展的限制。有必要了解HIV蛋白酶及其耐药突变体作用的分子基础，以开发新的抑制剂和新的治疗策略。晶体结构和底物特异性的分析已被用于确定重要的底物-蛋白酶相互作用和对底物识别至关重要的蛋白酶残基。预测这些关键残基存在于HIV蛋白酶的抑制剂抗性变体中，并且是已知抗性变体中最常见的突变残基。在耐药分离株中发现的HIV-1蛋白酶突变体的结构和活性已被表征。PI小组的分析表明，耐药突变体具有改变的催化活性和切割代表多蛋白加工中关键步骤的肽的特异性，以及改变的二聚体稳定性。预期所有这些作用都有助于在蛋白酶抑制剂存在下增加病毒复制。 已经开发了计算方法来预测HIV蛋白酶肽底物切割的相对效率和蛋白酶突变体的相对抑制。将比较临床抑制剂，以确定对改善耐药蛋白酶变体抑制的重要因素。基于结构的设计将有助于开发新的蛋白酶抑制剂，作为下一代抗病毒剂，以克服耐药性。

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.