Structure Based Thermodynamic Studies of HIV-1 Protease

描述（由申请人提供）： 蛋白酶抑制剂是HIV/AIDS化疗的关键成分。不幸的是，蛋白酶抑制剂的长期功效被耐药性突变的出现严重损害，所述耐药性突变将其效力降低到不足以有效抑制和病毒抑制的水平。耐药性的发生通常会因患者依从性问题而加速，并经常因严重的副作用而加剧。此外，在非洲流行的病毒亚型，绝大多数艾滋病毒感染发生在非洲，与导致美洲和欧洲感染的病毒亚型不同。使事情更加复杂的是，另一种艾滋病毒，HIV-2，虽然不如HIV-1流行，但也能引起艾滋病。显然，开发具有高效力、针对不同亚型的有效性、对突变的低敏感性和最小副作用的新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开发精确的热力学和结构指南，以开发此类抑制剂。 该项目的具体目标是： - 鉴定具有极高亲和力的热力学和结构决定因素。 - 鉴定赋予蛋白酶抑制剂对突变的低敏感性和对不同病毒亚型（包括HIV-2）的有效性的热力学和结构决定因素。 - 确定热力学和结构决定因素，降低蛋白酶抑制剂对不需要的靶标的亲和力，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）、结构测定（X射线晶体学）和基于结构的热力学分析的组合来实现。

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.