RATIONAL DESIGN AND SYNTHESIS OF A NOVEL CLASS OF ACTIVE SITE-TARGETED HIV PROTEASE INHIBITORS CONTAINING A HYDROXYMETHYLCARBONYL ISOSTERE. USE OF PHENYLNORSTATINE OR ALLOPHENYLNORSTATINE AS A TRANSITION-STATE MIMIC

Abstract

A novel class of HIV-1 protease inhibitors containing a hydroxymethylcarbonyl (HMC) isostere were designed from the substrate transition state and synthesized. Phenylnorstatine [Pns; (2R, 3S)-3-amino-2-hydroxy-4-phenylbutyric acid] and the 2S diastereomer, (2S, 3S)-3-amino-2-hydroxy-4-phenylbutyric acid, named allophenylnorstatine (Apns) were effective transition-state mimics, and incorporation of Pns-Pro or Apns-Pro at the P₁-P₁' site gave potent and specific HIV-1 protease inhibitors. In the inhibitory assays, the chemically synthesized [Ala^{67, 95}] HIV-1 protease was used.