COMPARATIVE BEHAVIOR OF CALPAIN AND CATHEPSIN-B TOWARD PEPTIDYL ACYLOXYMETHYL KETONES, SULFONIUM METHYL KETONES AND OTHER POTENTIAL INHIBITORS OF CYSTEINE PROTEINASES

Peptidyl acyloxymethyl ketones, previously established as potent inactivators of the lysosomal cysteine proteinase cathepsin B, were evaluated against smooth-muscle calpain. a member of the family of Ca2+-dependent cysteine proteinases. Only modest rates of time-dependent inhibition could be achieved, even with peptidyl affinity groups optimized for calpain and linked to a carboxylate leaving group of very low pK(a) [2,6-(CF3)2PhCOO-, pK(a) 0.58]. Selective inactivation of cathespin B versus calpain was Consistently observed with this type of inhibitor. Examination of other potential inhibitors revealed a rank order of potency against calpain to be: peptidyl sulphonium methyl ketones > fluoromethyl ketones, diazomethyl ketones much greater than acyloxymethyl ketones, an order which differs sharply from that found for cathespin B.