Effect of hydroxyl group configuration in hydroxyethylamine dipeptide isosteres on HIV protease inhibition. Evidence for multiple binding modes.

Inhibition of HIV-1 protease (HIV-PR), the aspartic protease that cleaves specific amide bonds in precursor gag-pol proteins to form the mature proteins needed for production of infectious human immunodeficiency virus (HIV) particles,' is regarded as a promising approach for treating acquired immunodeficiency syndrome (AIDS) and related diseases. Tight-binding inhibitors of HIV-PR have been discovered quickly2-10 because the principles for inhibiting this class of enzyme were known from earlier studies of inhibitors of renin and other aspartic proteinases.11J2 One structural feature present in most tightbinding aspartic protease inhibitors is a critical hydroxyl group that hydrogen bonds to the catalytically active aspartic acid carboxyl groups in a mechanistically related fashion."J2 Structure-activity data indicate that an (S)-hydroxyl is preferred,13 and to date, all crystal structures of chiral inhibitors bound to fungal aspartic pro-