title: Inhibition of arginine gingipains (RgpB and HRgpA) with benzamidine inhibitors: zinc increases inhibitory potency.
abstract: We assayed several benzamidine derivatives for inhibition potency with HRgpA and RgpB gingipains, enzymes which are involved in the pathogenesis of gingivitis and periodontal disease. The benzamidine derivatives proved to be effective inhibitors of HRgpA and RgpB, with the best inhibitor being a bis-benzamidine with a urea linker (Ki=30 microM). The inhibition potency was increased 2-3 fold in the presence of low concentrations of zinc with the benzamidines containing a urea moiety linking the two aromatic rings. We propose an inhibition model involving a tetrahedral zinc atom coordinated with the active site Cys and His of gingipain and the urea linker in the benzamidine inhibitor. In summary, we have discovered a new series of effective inhibitors for the gingipains and found a novel way to increase inhibitor potency with the HRgpA and RgpB gingipains using zinc.
authors.affiliation: School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta 30093-0400, USA.
authors.forename: Joel A
authors.initials: JA
authors.lastname: Krauser
authors.forename: Jan
authors.initials: J
authors.lastname: Potempa
authors.forename: James
authors.initials: J
authors.lastname: Travis
authors.forename: James C
authors.initials: JC
authors.lastname: Powers
mesh_terms: D018829:Adhesins, Bacterial; D001550:Benzamidines / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D003432:Cross-Linking Reagents; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D000080867:Gingipain Cysteine Endopeptidases; D006388:Hemagglutinins / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D013329:Structure-Activity Relationship; D014508:Urea; D015032:Zinc / Q000737:chemistry / Q000494:pharmacology
chemical_list: D018829:Adhesins, Bacterial; D001550:Benzamidines; D003432:Cross-Linking Reagents; D000080867:Gingipain Cysteine Endopeptidases; D006388:Hemagglutinins; D011480:Protease Inhibitors; D014508:Urea; D003546:Cysteine Endopeptidases; D015032:Zinc