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疗效受到耐药性突变的严重损害，这些突变使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。此外，在非洲流行的病毒亚型与在美国和欧洲引起感染的病毒亚型不同，而非洲是绝大多数艾滋病毒感染的发生地。更复杂的是，另一种HIV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、对突变易感性低、副作用小的新型蛋白酶抑制剂仍然是一个迫切的目标。该项目的主要目标是制定精确的热力学和结构准则，以开发此类抑制剂。

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.