ACTIVITY OF RESISTANT VARIANTS OF HIV PROTEASE

描述(改编自申请人摘要)：需要 了解HIV蛋白酶及其作用的分子基础 抗药性变种，以开发新的抑制剂和新的 治疗策略。此前，晶体的比对 两种截然不同的逆转录病毒的结构和特异性 用来自HIV和Rous肉瘤病毒(RSV)的酶来鉴定 重要的抑制物-蛋白酶相互作用和 对底物的识别至关重要。对这些关键残基进行了预测 出现在HIV蛋白酶的抗药性变种中，并且是 已知的耐药变异株中最常见的突变残基。的变种 将对HIV-1和RSV蛋白酶进行研究，以模拟 对抑制剂产生抗药性。这些化合物的晶体结构 将确定不同的蛋白质，它们对多肽的特异性 代表天然多蛋白裂解位点的底物将是 我们将研究它们对病毒复制的影响。新的 将评估抑制剂抑制HIV蛋白酶的能力。 变异体及其抗病毒作用。计算方法一直是 开发的预测HIV多肽底物相对效率的方法 蛋白酶。这些计算将被用来预测 多蛋白裂解和病毒复制的抗性突变体 不同抑制剂的活性。一个主要的优势是，这些 预测将适用于任何新发现的抗病突变体 HIV蛋白酶，并将有助于设计新的抑制剂来克服耐药性。

DESCRIPTION (Adapted from Applicant's Abstract): It is necessary to understand the molecular basis for the action of HIV protease and its inhibitor-resistant variants in order to develop new inhibitors and new therapeutic strategies. Previously, the comparison of the crystal structures and specificities of two distinctly different retroviral proteases from HIV and Rous sarcoma virus (RSV) were 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 the most commonly mutated residues in the known resistant variants. Variants of both HIV-1 and RSV proteases will be studied in order to model the development of resistance to inhibitors. The crystals structures of these variant proteins will be determined, their specificities for peptide substrates representing the natural polyprotein cleavage sites will be measured, and their effects on viral replication will be studied. New inhibitors will be evaluated for their ability to inhibit HIV protease variants and for their antiviral effects. Computational methods have been developed that predict the relative efficiency of peptide substrates of HIV protease. These calculations will be used to predict the effects of the resistant mutants on cleavage of the polyproteins and viral replication and the activity of different inhibitors. One major advantage is that these predictions will be applicable to any newly discovered resistant mutants of HIV protease, and will help to design new inhibitors to overcome resistance.