Beck Zachary Q, Morris Garrett M, Elder John H
Department of Molecular Biology, Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037, USA.
Curr Drug Targets Infect Disord. 2002 Mar;2(1):37-50. doi: 10.2174/1568005024605837.
The Aspartyl protease of HIV-1 offers an excellent target for the development of specific drugs against the virus. Drugs against protease and reverse transcriptase form the basis for Highly Active Anti-Retroviral Therapy (HAART) that has been successful in improving survival rates and quality of life for HIV infected individuals. However, resistance development to these drugs is a continuing problem, demanding development of additional drugs and approaches to fight virus infection. A thorough understanding of the molecular basis for substrate and inhibitor specificity is critical to defining mechanisms of evasion by drug-resistant mutants as well as for the rational design of drugs able to inhibit a broad spectrum of HIV-1 variants. In this article, we describe characteristics of the protease structure and what is known regarding substrate diversity and mechanisms of cleavage. Approaches to defining substrate diversity are described as an approach to identifying optimal templates for broad-based inhibitor development.
HIV-1的天冬氨酰蛋白酶为开发针对该病毒的特效药物提供了一个绝佳靶点。抗蛋白酶和抗逆转录酶药物构成了高效抗逆转录病毒疗法（HAART）的基础，该疗法已成功提高了HIV感染者的生存率和生活质量。然而，对这些药物产生耐药性仍是一个持续存在的问题，这就需要开发更多药物和方法来对抗病毒感染。深入了解底物和抑制剂特异性的分子基础，对于明确耐药突变体的逃避机制以及合理设计能够抑制多种HIV-1变体的药物至关重要。在本文中，我们描述了蛋白酶结构的特征以及关于底物多样性和切割机制的已知信息。定义底物多样性的方法被描述为一种识别广泛抑制剂开发最佳模板的途径。
