부산대학교 도서관

Hyperactivationof the calcium-dependent cysteine protease calpain1 (Cal1) is implicated as a primary or secondary pathological eventin a wide range of illnesses and in neurodegenerative states, includingAlzheimer’s disease (AD). E-64 is an epoxide-containing naturalproduct identified as a potent nonselective, calpain inhibitor, withdemonstrated efficacy in animal models of AD. By use of E-64 as alead, three successive generations of calpain inhibitors were developedusing computationally assisted design to increase selectivity forCal1. First generation analogues were potent inhibitors, effectingcovalent modification of recombinant Cal1 catalytic domain (Cal1cat), demonstrated using LC–MS/MS. Refinement yieldedsecond generation inhibitors with improved selectivity. Further libraryexpansion and ligand refinement gave three Cal1 inhibitors, one ofwhich was designed as an activity-based protein profiling probe. Thesewere determined to be irreversible and selective inhibitors by kineticsstudies comparing full length Cal1 with the general cysteine proteasepapain. [ABSTRACT FROM AUTHOR]