New approaches to HIV protease inhibitor drug design II: testing the substrate envelope hypothesis to avoid drug resistance and discover robust inhibitorsNalam, Madhavi NL; Schiffer, Celia ACurrent Opinion in HIV and AIDS: November 2008 - Volume 3 - Issue 6 - p 642–646 doi: 10.1097/COH.0b013e3283136cee HIV protease inhibitors: Edited by Jon Schapiro and John Erickson Abstract Author Information Purpose of review Drug resistance results when the balance between the binding of inhibitors and the turnover of substrates is perturbed in favor of the substrates. Resistance is quite widespread to the HIV-1 protease inhibitors permitting the protease to process its 10 different substrates. This processing of the substrates permits the virus HIV-1 to mature and become infectious. The design of HIV-1 protease inhibitors that closely fit within the substrate-binding region is proposed to be a strategy to avoid drug resistance. Recent findings Cocrystal structures of HIV-1 protease with its substrates define an overlapping substrate-binding region or substrate envelope. Novel HIV-1 protease inhibitors that were designed to fit within this substrate envelope were found to retain high binding affinity and have a flat binding profile against a panel of drug-resistant HIV-1 proteases. Summary The avoidance of drug resistance needs to be considered in the initial design of inhibitors to quickly evolving targets such as HIV-1 protease. Using a detailed knowledge of substrate binding appears to be a promising strategy for achieving this goal to obtain robust HIV-1 protease inhibitors. Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, USA Correspondence to Dr Celia A. Schiffer, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA Tel: +1 508 856 8008; fax: +1 508 856 6464; e-mail: Celia.Schiffer@umassmed.edu © 2008 Lippincott Williams & Wilkins, Inc.