STUDIES OF HIV-1 PROTEASE INHIBITORS .2. INCORPORATION OF 4 TYPES OF HYDROXYETHYLENE DIPEPTIDE ISOSTERES AT THE SCISSILE SITE OF SUBSTRATE SEQUENCES

Human immunodeficiency virus type 1 (HIV-1) protease inhibitors contai ning four types of hydroxyethylene dipeptide isosteres were designed a nd synthesized. These inhibitors consist of eight stereoisomers of phe nylalanylproline (Phe-psi[H.E.]-Pro), four stereoisomers of phenylalan ylalanine (Phe-psi[H.E.]-Ala), and one stereoisomer each of phenylalan ylglycine (Phe-psi[H.E.1-Gly) and cyclohexylalanylalanine (Cha-psi[H.E .]-Ala) hydroxyethylene dipeptide isosteres. For the synthesis of the latter two isosteres, a newly developed synthetic method for gamma-lac tone was applied. The inhibitory activities of these peptides were eva luated by cleavage assay of partially purified gag proteins or purifie d synthetic peptide. Of the inhibitors examined, compounds 2c (Z-Asn-( 2S,3R,4S,5S)-Phe-psi[H.E.]-Pro-NHBu(n); Bu(n)=n-butyl, K(i)=0.50 mum), 21a (Z-Asn-(2R,4S,5S)-Phe-psi[H.E.]-Ala-NHBu(n), K(i)=0.34 mum) and 2 3 (Z-Asn-(2R,4S,5S)-Cha-psi[H.E.]-Ala-NHBu(n), K(i) = 0.46 mum) were m oderately potent inhibitors. The results revealed that the alkyl subst ituent at C2 is essential, and the stereochemistry of the hydroxyethyl ene dipeptide isosteres greatly affected their inhibitory activities.