title: Studies of HIV-1 protease inhibitors. I. Incorporation of a reduced peptide, simple aminoalcohol, and statine analog at the scissile site of substrate sequences.
abstract: Inhibitors of the protease of human immunodeficiency virus type-1 (HIV-1) were designed and synthesized. A reduced peptide, simple aminoalcohol, and statine analog, 4-amino-3-hydroxy-5-phenylpentanoic acid (AHPPA), were inserted at the scissile site of substrate sequences of HIV-1 protease. While both reduced peptides and simple aminoalcohol derivatives were weak inhibitors, the peptides containing AHPPA demonstrated moderate inhibitory activity. The more potent alcohol configuration of AHPPA is (R), which is opposite to the configuration in potent inhibitors of other aspartic proteases. In particular, compound 28 ((3R,4S)-4-(N-tert-butoxycarbonyl- L-glutaminyl-L-asparaginyl)amino-3-hydroxy-5-phenylpentanoic acid 2'-methylbutylamide) had a Ki of 0.36 microM and exhibited excellent enzyme specificity.
authors.affiliation: New Lead Research Laboratory, Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Sakurai
authors.forename: M
authors.initials: M
authors.lastname: Sugano
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
authors.forename: Y
authors.initials: Y
authors.lastname: Yabe
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry* / Q000494:pharmacology; D000605:Amino Alcohols / Q000737:chemistry*; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D010455:Peptides / Q000737:chemistry*; D013379:Substrate Specificity
chemical_list: D000596:Amino Acids; D000605:Amino Alcohols; D017320:HIV Protease Inhibitors; D010455:Peptides; C049986:4-amino-3-hydroxy-5-phenylpentanoic acid; C013165:statine