Biomaterial Database

Molecular Basis for Drug Resistance in HIV-1 Protease. 2010

Akbar Ali, and Rajintha M Bandaranayake, and Yufeng Cai, and Nancy M King, and Madhavi Kolli, and Seema Mittal, and Jennifer F Murzycki, and Madhavi N L Nalam, and Ellen A Nalivaika, and Ayşegül Özen, and Moses M Prabu-Jeyabalan, and Kelly Thayer, and Celia A Schiffer

Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.

HIV-1 protease is one of the major antiviral targets in the treatment of patients infected with HIV-1. The nine FDA approved HIV-1 protease inhibitors were developed with extensive use of structure-based drug design, thus the atomic details of how the inhibitors bind are well characterized. From this structural understanding the molecular basis for drug resistance in HIV-1 protease can be elucidated. Selected mutations in response to therapy and diversity between clades in HIV-1 protease have altered the shape of the active site, potentially altered the dynamics and even altered the sequence of the cleavage sites in the Gag polyprotein. All of these interdependent changes act in synergy to confer drug resistance while simultaneously maintaining the fitness of the virus. New strategies, such as incorporation of the substrate envelope constraint to design robust inhibitors that incorporate details of HIV-1 protease's function and decrease the probability of drug resistance, are necessary to continue to effectively target this key protein in HIV-1 life cycle.