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.
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.
Poe
M
M
Department of Enzymology, Merck Sharp and Dohme Research Laboratories, Rahway, New Jersey 07065.
Wu
J K
JK
Blake
J T
JT
Zweerink
H J
HJ
Sigal
N H
NH
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*
D001550:Benzamidines; D006146:Guanidines; D015842:Serine Proteinase Inhibitors; D053804:Granzymes; D012697:Serine Endopeptidases; C509212:GZMA protein, human; C032855:nafamostat