Development and Therapeutic Potential of Calpain Inhibitors

Abstract

This chapter presents evidence that calpain over activation may be a key component in a number of disorders. The common theme for most of these disorders is cellular Ca 2+ overload. The calpains can be found in the cytosolic compartment and can also be identified in the plasma membrane and other organelle membranes. Both isoforms contain two subunits. Calpain appears to be an ideal pharmaceutical target, as this protease is most active during pathological events. The current challenge is to identify cell-permeable and selective calpain inhibitors for evaluation in various in vivo disease models. As the knowledge of calpain substrate specificity is increasing and calpain inhibitors from natural products screening programs are becoming available, more selective inhibitors are designed and synthesized. At present there is an arsenal of calpain inhibitors for disposal. These inhibitors include protein inhibitors, such as calpastatin, irreversible peptide inhibitors, such as E64 analogs, reversible peptide inhibitors, such as peptidyl α-keto amides, and several nonpeptide inhibitors. With the recent emergence of several cell-permeable calpain selective inhibitors, the goal of understanding the physiological roles of calpain are possible to be achievable.