title: The enzymatic activity of human cytotoxic T-lymphocyte granzyme A and cytolysis mediated by cytotoxic T-lymphocytes are potently inhibited by a synthetic antiprotease, FUT-175.
abstract: The synthetic antiprotease, FUT-175 (6-amidino-2-naphthyl-4-guanidinobenzoate), was found to be an extraordinarily potent and rapid inhibitor of human Q31 cytotoxic T-lymphocyte granzyme A. The granzyme A was inhibited in a time-dependent manner with kobs/i = 430,000 +/- 80,000 M-1 s-1. Four other FUT-175 analogs were also found to be potent, rapid Q31 granzyme A inhibitors. All five compounds inhibited Q31 cytotoxic T-lymphocyte-mediated cytolysis of human JY lymphoma cells, but at concentrations far in excess of those needed for granzyme A inhibition. The data presented suggest that postmarketing surveillance of FUT-175 should include a review of possible immunosuppressive side-effects, such as increased susceptibility to viral infections and to neoplastic transformations.
authors.affiliation: Department of Enzymology, Merck Sharp and Dohme Research Laboratories, Rahway, New Jersey 07065.
authors.forename: M
authors.initials: M
authors.lastname: Poe
authors.forename: J K
authors.initials: JK
authors.lastname: Wu
authors.forename: J T
authors.initials: JT
authors.lastname: Blake
authors.forename: H J
authors.initials: HJ
authors.lastname: Zweerink
authors.forename: N H
authors.initials: NH
authors.lastname: Sigal
mesh_terms: D001550:Benzamidines; D003602:Cytotoxicity, Immunologic; D053804:Granzymes; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D007111:Immunity, Cellular; D066298:In Vitro Techniques; D007700:Kinetics; D012697:Serine Endopeptidases; D015842:Serine Proteinase Inhibitors; D013329:Structure-Activity Relationship; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D001550:Benzamidines; D006146:Guanidines; D015842:Serine Proteinase Inhibitors; D053804:Granzymes; D012697:Serine Endopeptidases; C509212:GZMA protein, human; C032855:nafamostat