1 research outputs found
Design, Synthesis, and Optimization of Novel Epoxide Incorporating Peptidomimetics as Selective Calpain Inhibitors
Hyperactivation
of the calcium-dependent cysteine protease calpain
1 (Cal1) is implicated as a primary or secondary pathological event
in a wide range of illnesses and in neurodegenerative states, including
Alzheimer’s disease (AD). E-64 is an epoxide-containing natural
product identified as a potent nonselective, calpain inhibitor, with
demonstrated efficacy in animal models of AD. By use of E-64 as a
lead, three successive generations of calpain inhibitors were developed
using computationally assisted design to increase selectivity for
Cal1. First generation analogues were potent inhibitors, effecting
covalent modification of recombinant Cal1 catalytic domain (Cal1<sub>cat</sub>), demonstrated using LC–MS/MS. Refinement yielded
second generation inhibitors with improved selectivity. Further library
expansion and ligand refinement gave three Cal1 inhibitors, one of
which was designed as an activity-based protein profiling probe. These
were determined to be irreversible and selective inhibitors by kinetics
studies comparing full length Cal1 with the general cysteine protease
papain