title: Episelection: novel Ki approximately nanomolar inhibitors of serine proteases selected by binding or chemistry on an enzyme surface.
abstract: A novel class of mechanism-based inhibitors of the serine proteases is developed using epitaxial selection. Tripeptide boronates esterified by an alcohol or alcohols at the boron retain the tight binding to trypsin-like enzymes associated with transition-state analogs and incorporate additional groups that can be utilized for selectivity between proteases. Formed by reaction of a series of alcohols with the inhibitor boronate oxygen(s), the most structurally compatible alcohol-derivatized inhibitors are either selected by binding to the enzyme (epitaxial selection) or assembled by epitaxial reaction on the enzyme surface. Mass spectrometry of the derivatized boronates and X-ray crystallography of the complexes identify the chemical structures and the three-dimensional interactions of inhibitors generated. This scheme also engineers novel, potent (Ki approximately 7 nM), and more specific inhibitors of individual serine proteases, by derivitizations of compounds obtained by epitaxial selection.
authors.affiliation: Arris Pharmaceutical Corporation, South San Francisco, California 94080, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Katz
authors.forename: J
authors.initials: J
authors.lastname: Finer-Moore
authors.forename: R
authors.initials: R
authors.lastname: Mortezaei
authors.forename: D H
authors.initials: DH
authors.lastname: Rich
authors.forename: R M
authors.initials: RM
authors.lastname: Stroud
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D001895:Boron; D018360:Crystallography, X-Ray; D007202:Indicators and Reagents; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D012680:Sensitivity and Specificity; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D014357:Trypsin / Q000737:chemistry* / Q000378:metabolism; D014361:Trypsin Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D007202:Indicators and Reagents; D009842:Oligopeptides; D015842:Serine Proteinase Inhibitors; D014361:Trypsin Inhibitors; D012697:Serine Endopeptidases; D014357:Trypsin; D001895:Boron