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Approaches to the design of HIV protease inhibitors with improved resistance profiles

Gulnik, Sergei V; Eissenstat, Michael

Current Opinion in HIV and AIDS: November 2008 - Volume 3 - Issue 6 - p 633–641
doi: 10.1097/COH.0b013e328313911d
HIV protease inhibitors: Edited by Jon Schapiro and John Erickson

Purpose of review This review describes current approaches to HIV protease inhibitor design, with a focus on improving their profile against drug-resistant mutants. Potential explanations for the flat resistance profile of some potent protease inhibitors and discrepancies between the apparent fold change of potency at the enzyme level and in cell-based assays are discussed.

Recent findings Despite new ideas and a clear rationale for designing inhibitors that bind outside the enzyme active site, all current protease inhibitors with potent antiviral activity target this site. Several bis-tetrahydrofuran-containing compounds including darunavir, brecanavir, GS-8374, and Sequoia protease inhibitors exhibit excellent potency against mutant HIV strains that are resistant to clinically used protease inhibitors. The apparently flat resistance profiles of these and some other protease inhibitors may, at least in part, be explained by their high potency against wild-type enzyme. The substrate envelope and solvent-anchoring hypotheses have been used to design and/or rationalize improved resistance profiles. Traditional approaches yielded a lysine sulfonamide PL-100 with a unique resistance profile.

Summary Several theories on how to design HIV protease inhibitors with improved resistance profiles have been proposed during the review period. The general concepts that are incorporated into most design strategies include maximizing the interactions with the backbone and conserved side chains of the enzyme while minimizing inhibitor size and maintaining conformational flexibility to allow for modified binding modes.

Sequoia Pharmaceuticals, Inc., Gaithersburg, Maryland, USA

Correspondence to Sergei V. Gulnik, Sequoia Pharmaceuticals, Inc., Suite 200, 401 Professional Drive, Gaithersburg, Maryland, USA Tel: +1 240 632 0094, ext. 201; fax: +1 240 632 0465; e-mail:

© 2008 Lippincott Williams & Wilkins, Inc.