title: Inhibition of proteases with enkephalin-analogue inhibitors.
abstract: N-peptidyl-O-acyl hydroxylamines have proven to be effective and selective mechanism-based inhibitors of serine and cysteine proteases as demonstrated using enzymes with specificities for hydrophobic amino acids at the cleavage site. Here, we report for the first time the inhibition of proteases able to accommodate cationic amino acid side chains in their binding pockets using compounds of this inhibitor class. Trypsin and papain are inactivated by enkephalin-analogue diacyl hydroxylamines in a time-dependent and irreversible manner exhibiting second-order rate constants in the range of 100-1000 M-1.s-1. In contrast, human cerebrospinal fluid dynorphin-converting enzyme (hCSFDCE) is inhibited only moderately by these inhibitors. Mechanistic implications have been derived.
authors.affiliation: Department of Biotechnology, Martin-Luther-University of Halle, Saale, Germany.
authors.forename: H U
authors.initials: HU
authors.lastname: Demuth
authors.forename: J
authors.initials: J
authors.lastname: Silberring
authors.forename: F
authors.initials: F
authors.lastname: Nyberg
mesh_terms: D000595:Amino Acid Sequence; D003546:Cysteine Endopeptidases / Q000187:drug effects*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D004745:Enkephalins / Q000494:pharmacology*; D006898:Hydroxylamines / Q000494:pharmacology*; D008969:Molecular Sequence Data; D010206:Papain / Q000187:drug effects*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D014357:Trypsin / Q000187:drug effects*
chemical_list: D015853:Cysteine Proteinase Inhibitors; D004745:Enkephalins; D006898:Hydroxylamines; D011480:Protease Inhibitors; D015842:Serine Proteinase Inhibitors; D004743:Enkephalin, Leucine; C026768:enkephalin-Leu, Arg(6)-; D014357:Trypsin; D003546:Cysteine Endopeptidases; C063078:dynorphin converting enzyme; D010206:Papain