Structure Based Thermodynamic Studies of HIV-1 Protease

描述(由申请人提供)： 蛋白水解酶抑制剂是HIV/AIDS化疗的关键成分。不幸的是，由于耐药突变的出现，使其效力降低到不足以有效抑制和抑制病毒的水平，严重影响了蛋白水解酶抑制剂的长期疗效。患者的依从性问题往往会加速耐药性的出现，严重的副作用往往会加剧这种情况。此外，在非洲流行的病毒亚型与导致美国和欧洲感染的病毒亚型不同，非洲是绝大多数艾滋病毒感染发生的地方。更复杂的是，一种不同的艾滋病毒，HIV-2，虽然没有HIV-1流行，但也能引起艾滋病。显然，开发高效、对不同亚型有效、对突变敏感性低、副作用最小的新的蛋白酶抑制剂仍然是一个紧迫的目标。该项目的主要目标是制定精确的热力学和结构指南来开发此类缓蚀剂。 该项目的具体目标是： -确定极高亲和力的热力学和结构决定因素。 -确定热力学和结构决定因素，使蛋白酶抑制剂对突变的敏感性较低，并对包括艾滋病毒-2在内的不同病毒亚型有效。 -确定热力学和结构决定因素，降低蛋白酶抑制剂对不想要的目标的亲和力，从而提高选择性并减少副作用。 这些目标将通过实验热力学测量(高灵敏度等温滴定量热法和高灵敏度差示扫描量热法)、结构确定(X射线结晶学)和基于结构的热力学分析相结合来实现。

DESCRIPTION (provided by applicant): Protease inhibitors are key components in the chemotherapy of HIV/AIDS. Unfortunately, the long term efficacy of protease inhibitors is severely compromised by the appearance of drug-resistant mutations that lower their potency to inadequate levels for effective inhibition and viral suppression. The onset of drug resistance is often accelerated by issues of patient compliance, often aggravated by severe side effects. In addition, the viral subtypes prevalent in Africa, where the vast majority of HIV infections take place, are not the same as the one responsible for the infections in America and Europe. Complicating things even further, a different HIV virus, HIV-2, although less prevalent than HIV-1, is also able to cause AIDS. It is evident, that the development of new protease inhibitors with high potency, effectiveness against different subtypes, low susceptibility to mutations and minimal side effects still remains an urgent goal. The main goal of this project is to develop precise thermodynamic and structural guidelines to develop such inhibitors. The specific goals of this project are: - Identification of thermodynamic and structural determinants of extremely high affinity. - Identification of thermodynamic and structural determinants that confer protease inhibitors low susceptibility to mutations and efficacy against different viral subtypes, including HIV-2. - Identification of thermodynamic and structural determinants that lower the affinity of protease inhibitors to unwanted targets and hence improve selectivity and reduce side effects. The goals will be achieved by a combination of experimental thermodynamic measurements (high sensitivity isothermal titration calorimetry and high sensitivity differential scanning calorimetry), structure determination (x-ray crystallography) and structure-based thermodynamic analysis.