title: Peptide substrates and inhibitors of the HIV-1 protease.
abstract: Oligopeptides containing the consensus retroviral protease cleavage sequence Ser/Thr-X-Y-Tyr/Phe-Pro are substrates for purified recombinant HIV-1 protease with Km's in the millimolar range. The minimum sequence containing the consensus pentapeptide which serves as a good substrate is a heptapeptide spanning the P4-P3' residues. Substitution of reduced Phe-Pro or Tyr-Pro dipeptide isosteres or the statine analog 3-hydroxy-4-amino-5-phenylpentanoic acid for the scissile dipeptide afforded inhibitors of HIV-1 protease with Ki values in the micromolar range, three orders of magnitude better in affinity than the corresponding substrates. Inhibitors of HIV-1 protease may provide a novel and potentially useful therapeutic approach to the treatment of acquired immune deficiency syndrome (AIDS).
authors.affiliation: Department of Peptide Chemistry, Smith Kline & French Laboratories, King of Prussia, PA 19406.
authors.forename: M L
authors.initials: ML
authors.lastname: Moore
authors.forename: W M
authors.initials: WM
authors.lastname: Bryan
authors.forename: S A
authors.initials: SA
authors.lastname: Fakhoury
authors.forename: V W
authors.initials: VW
authors.lastname: Magaard
authors.forename: W F
authors.initials: WF
authors.lastname: Huffman
authors.forename: B D
authors.initials: BD
authors.lastname: Dayton
authors.forename: T D
authors.initials: TD
authors.lastname: Meek
authors.forename: L
authors.initials: L
authors.lastname: Hyland
authors.forename: G B
authors.initials: GB
authors.lastname: Dreyer
authors.forename: B W
authors.initials: BW
authors.lastname: Metcalf
mesh_terms: D000595:Amino Acid Sequence; D010450:Endopeptidases / Q000378:metabolism; D016333:HIV Protease; D006868:Hydrolysis; D007700:Kinetics; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis / Q000378:metabolism*; D011480:Protease Inhibitors; D011994:Recombinant Proteins / Q000378:metabolism; D012191:Retroviridae Proteins / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D009842:Oligopeptides; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D012191:Retroviridae Proteins; D010450:Endopeptidases; D016333:HIV Protease