Studies of HIV-1 Protease Inhibitors. II.Incorporation of Four Types of Hydroxyethylene Dipeptide Isosteres at the Scissile Site of Substrate Sequences

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Human immunodeficiency virus type 1 (HIV-1) protease inhibitors containing four types of hydroxyethylene dipeptide isosteres were designed and synthesized. These inhibitors consist of eight stereoisomers of phenylalanylproline (Phe-ψ[H.E.]-Pro), four stereoisomers of phenylalanylalanine (Phe-ψ[H.E.]-Ala), and one stereoisomer each of phenylalanylglycine (Phe-ψ[H.E.]-Gly) and cyclohexylalanylalanine (Che-ψ[H.E.]-Ala) hydroxyethylene dipeptide isosteres. For the synthesis of the latter two isosteres, a newly developed synthetic method for γ-lactone was applied. The inhibitory activities of these peptides were evaluated by cleavage assay of partially purified gag proteins or purified synthetic peptide. Of the inhibitors examined, compounds 2c (Z-Asn-(2S, 3R, 4S, 5S)-Phe-ψ[H.E.]-Pro-NHBu^n; Bu^n=n-butyl, K_i=0.50μM), 21a (Z-Asn-(2R, 4S, 5S)-Phe-ψ[H.E.]-Ala-NHBu^n, K_i=0.34μM) and 23 (Z-Asn-(2R, 4S, 5S)-Cha-ψ[H.E.]-Ala-NHBu^n, K_i=0.46μM) were moderately potent inhibitors. The results revealed that the alkyl substituent at C2 is essential, and the stereochemistry of the hydroxyethylene dipeptide isosteres greatly affected their inhibitory activities.
社団法人日本薬学会の論文
1993-08-15