Molecular Basis for Drug Resistance in HIV-1 Protease

Overview

Journal Viruses

Publisher MDPI

Specialty Microbiology

Date 2011 Oct 14

PMID 21994628

Citations 63

Authors

Akbar Ali

Rajintha M Bandaranayake

Yufeng Cai

Nancy M King

Madhavi Kolli

Seema Mittal

Jennifer F Murzycki

Madhavi N L Nalam

Ellen A Nalivaika

Aysegul Ozen

Moses M Prabu-Jeyabalan

Kelly Thayer

Celia A Schiffer

Affiliations

Soon will be listed here.

Abstract

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.

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