title: Studies of HIV-1 protease inhibitors. II. Incorporation of four types of hydroxyethylene dipeptide isosteres at the scissile site of substrate sequences.
abstract: 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-psi[H.E.]-Pro), four stereoisomers of phenylalanylalanine [Phe-psi[H.E.]-Ala), and one stereoisomer each of phenylalanylglycine (Phe-psi[H.E.]-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-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-psi[H.E.]-Pro-NHB(un); Bu(n) = n-butyl, Ki = 0.50 microM), 21a (Z-Asn-(2R,4S,5S)-Phe-psi[H.E.]-Ala- NHBu(n), Ki = 0.34 microM) and 23 (Z-Asn-(2R,4S,5S)-Cha-psi[H.E.]-Ala- NHBu(n), Ki = 0.46 microM) 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.
authors.affiliation: Bioscience Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Sakurai
authors.forename: S
authors.initials: S
authors.lastname: Higashida
authors.forename: M
authors.initials: M
authors.lastname: Sugano
authors.forename: T
authors.initials: T
authors.lastname: Nishi
authors.forename: F
authors.initials: F
authors.lastname: Saito
authors.forename: Y
authors.initials: Y
authors.lastname: Ohata
authors.forename: H
authors.initials: H
authors.lastname: Handa
authors.forename: T
authors.initials: T
authors.lastname: Komai
authors.forename: R
authors.initials: R
authors.lastname: Yagi
authors.forename: T
authors.initials: T
authors.lastname: Nishigaki
mesh_terms: D000595:Amino Acid Sequence; D004151:Dipeptides / Q000737:chemistry*; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D008969:Molecular Sequence Data; D013237:Stereoisomerism
chemical_list: D004151:Dipeptides; D017320:HIV Protease Inhibitors