title: Inhibition of human immunodeficiency virus 1 protease in vitro: rational design of substrate analogue inhibitors.
abstract: Inhibitors of the protease from human immunodeficiency virus 1 (HIV-1) were designed, synthesized, and kinetically characterized. Analogues of a heptapeptide substrate of HIV-1 protease with sequence similar to the p17-p24 cleavage site in the natural substrate, Pr55gag, were synthesized in which the scissile dipeptide bond was replaced with bonds from six categories of stable mimics of an aspartic proteolysis transition state or intermediate. These mimics included an analogue of statine, hydroxyethylene isosteres, two categories of phosphinic acids, a reduced amide isostere, and an alpha,alpha-difluoroketone. The resulting peptide analogues were linear competitive inhibitors of purified recombinant HIV-1 protease with inhibition constants ranging from 18 nM to 40 microM depending on the type of inhibitor. A truncated inhibitor, an analogue of a hexapeptide, retained full inhibitory potency. The most potent inhibitors, containing the hydroxyethylene isostere, effectively blocked the proteolytic processing of a recombinant form of Pr55gag by HIV-1 protease in a cell-free assay.
authors.affiliation: Department of Medicinal Chemistry, Smith Kline & French Laboratories, King of Prussia, PA 19406-0939.
authors.forename: G B
authors.initials: GB
authors.lastname: Dreyer
authors.forename: B W
authors.initials: BW
authors.lastname: Metcalf
authors.forename: T A
authors.initials: TA
authors.lastname: Tomaszek
authors.forename: T J
authors.initials: TJ
authors.lastname: Carr
authors.forename: A C
authors.initials: AC
authors.lastname: Chandler
authors.forename: L
authors.initials: L
authors.lastname: Hyland
authors.forename: S A
authors.initials: SA
authors.lastname: Fakhoury
authors.forename: V W
authors.initials: VW
authors.lastname: Magaard
authors.forename: M L
authors.initials: ML
authors.lastname: Moore
authors.forename: J E
authors.initials: JE
authors.lastname: Strickler
mesh_terms: D000595:Amino Acid Sequence; D015195:Drug Design; D004926:Escherichia coli / Q000235:genetics; D015497:HIV-1 / Q000201:enzymology* / Q000235:genetics; D007700:Kinetics; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D010447:Peptide Hydrolases / Q000235:genetics; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D009842:Oligopeptides; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D010447:Peptide Hydrolases