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Molecular Basis for Drug Resistance in HIV-1 Protease

Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA
Department of Pediatrics, University of Rochester, Rochester, NY 14627, USA
Division of Basic Sciences, The Commonwealth Medical College, 150 N. Washington Avenue, Scranton, PA 18503, USA
Author to whom correspondence should be addressed.
Viruses 2010, 2(11), 2509-2535;
Received: 8 October 2010 / Revised: 22 October 2010 / Accepted: 28 October 2010 / Published: 12 November 2010
(This article belongs to the Special Issue HIV Drug Resistance 2010)
PDF [946 KB, uploaded 12 May 2015]


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.
Keywords: drug resistance; HIV-1 protease; protease inhibitors; substrate envelope; structure based drug design drug resistance; HIV-1 protease; protease inhibitors; substrate envelope; structure based drug design
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Ali, A.; Bandaranayake, R.M.; Cai, Y.; King, N.M.; Kolli, M.; Mittal, S.; Murzycki, J.F.; Nalam, M.N.; Nalivaika, E.A.; Özen, A.; Prabu-Jeyabalan, M.M.; Thayer, K.; Schiffer, C.A. Molecular Basis for Drug Resistance in HIV-1 Protease. Viruses 2010, 2, 2509-2535.

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