hiv-1 protease structural perspectives on drug resistancehiv - 1蛋白酶结构角度对耐药性.pdfVIP

Viruses 2009, 1, 1110-1136; doi:10.3390/v1031110 OPEN ACCESS viruses ISSN 1999-4915 /journal/viruses Review HIV-1 Protease: Structural Perspectives on Drug Resistance Irene T. Weber * and Johnson Agniswamy Department of Biology, Molecular Basis of Disease Program, Georgia State University, Atlanta, GA 30303, USA; E-Mail: jagniswamy@ * Author to whom correspondence should be addressed; E-Mail: iweber@; Tel.: +1-404-413-5411; Fax: +1-404-413-5301. Received: 1 October 2009; in revised form: 30 November 2009 / Accepted: 1 December 2009 / Published: 3 December 2009 Abstract: Antiviral inhibitors of HIV-1 protease are a notable success of structure-based drug design and have dramatically improved AIDS therapy. Analysis of the structures and activities of drug resistant protease variants has revealed novel molecular mechanisms of drug resistance and guided the design of tight-binding inhibitors for resistant variants. The plethora of structures reveals distinct molecular mechanisms associated with resistance: mutations that alter the protease interactions with inhibitors or substrates; mutations that alter dimer stability; and distal mutations that transmit changes to the active site. These insights will inform the continuing design of novel antiviral inhibitors targeting resistant strains of HIV. Keywords: protease inhibitors; drug resistance; aspartic protease; molecular mechanism; darunavir 1. Introduction The structures and activities of HIV protease and its