Structure Based Thermodynamic Studies of HIV-1 Protease

基于结构的 HIV-1 蛋白酶热力学研究

基本信息

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
项目类别：
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

项目摘要

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）：蛋白酶抑制剂是艾滋病毒/艾滋病化疗的关键成分。不幸的是，蛋白酶抑制剂的长期功效因耐药突变的出现而受到严重损害，这些突变将其效力降低到不足以有效抑制和病毒抑制的水平。患者依从性问题往往会加速耐药性的发生，严重的副作用往往会加剧耐药性的发生。此外，绝大多数艾滋病毒感染发生在非洲，那里流行的病毒亚型与美洲和欧洲的病毒亚型并不相同。使事情变得更加复杂的是，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，开发高效、针对不同亚型、对突变的敏感性低和副作用最小的新型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突变的低敏感性以及对不同病毒亚型（包括 HIV-2）的功效。 - 鉴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结合来实现。