Structure Based Thermodynamic Studies of HIV-1 Protease

基于结构的 HIV-1 蛋白酶热力学研究

• 批准号: 7028375
• 负责人: Ernesto Freire
• 金额: $ 51.9万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7028375
• 关键词: X ray crystallography; antiAIDS agent; calorimetry; chemical binding; drug design /synthesis /production; drug resistance; drug screening /evaluation; endopeptidases; enzyme activity; gene mutation; genetic strain; human immunodeficiency virus 1; human immunodeficiency virus 2; protease inhibitor; protein structure; spectrometry; thermodynamics; virus protein

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.

描述（由申请人提供）： 蛋白酶抑制剂是HIV/AIDS化学疗法的关键组成部分。不幸的是，蛋白酶抑制剂的长期疗效因抗药性突变的出现而严重损害，从而降低了其效力不足，从而有效抑制和病毒抑制。耐药性的发作通常会因患者依从性问题而加速，这通常会因严重的副作用而加剧。此外，绝大多数艾滋病毒感染发生的非洲病毒亚型与对美国和欧洲的感染负有责任的人不同。使事情更加复杂，尽管不及HIV-1，但一种不同的HIV病毒HIV-2也能够引起艾滋病。显然，具有高效力，对不同亚型有效性，对突变的敏感性低和最小副作用的新蛋白酶抑制剂的发展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这种抑制剂。 该项目的具体目标是： - 鉴定极高亲和力的热力学和结构决定因素。 - 鉴定热力学和结构决定因素，这些决定因素赋予蛋白酶抑制剂对包括HIV-2在内的不同病毒亚型的突变和功效的敏感性低。 - 鉴定降低蛋白酶抑制剂对不需要靶标的亲和力的热力学和结构决定因素，从而提高了选择性并降低副作用。 实验热力学测量（高灵敏度等温滴定热量法和高灵敏度差异扫描量热法），结构测定（X射线晶体学）和基于结构的热力学分析的结合将实现目标。