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 k obs 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 Tlymphocyte-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.