Calpain Inhibition: A Therapeutic Strategy Targeting Multiple Disease States

Abstract

The calpains represent a well-conserved family of calcium-dependent cysteine proteases. They consist of several ubiquitous and tissue specific isoforms and exhibit broad substrate specificity influencing many aspects of cell physiology including migration, proliferation and apoptosis. Calpain activity in vivo is tightly regulated by its natural endogenous inhibitor calpastatin. Calpastatin specifically inhibits calpain and not other cysteine proteases by interaction with several sites on the calpain molecule. Inappropriate regulation of the calpain-calpastatin proteolytic system is associated with several important human pathological disorders including muscular dystrophy, cancer, Alzheimer's disease, neurological injury, ischaemia/reperfusion injury, atherosclerosis, diabetes and cataract formation. Recent advances in elucidating the tertiary structures of calpain 2 and its regulatory domain calpain 4, together with identification of new modes of regulating calpain activity provide new opportunities for the design of novel calpain inhibitors. Several classes of inhibitors, including peptidyl epoxide, aldehyde, and ketoamide inhibitors, targeting the active site have proven effective against the calpains and are in the process of evaluation in animal models of human disease. However, a major limitation to the clinical use of such inhibitors is their lack of specificity among cysteine proteases and other proteolytic enzymes. The development of a new class of calpain inhibitors that interact with domains outside of the catalytic site of calpain may provide greater specificity and therapeutic potential.

Calpain inhibition rescues troponin T3 fragmentation, increases Cav1.1 , and enhances skeletal muscle force in aging sedentary mice

“…BDA‐410 is a synthetic Leu‐Leu peptidomimetic that significantly attenuates various disease conditions (Carragher, 2006), including memory and synaptic transmission in a mouse model of Alzheimer disease and signs of premature aging in a mouse model of kotho deficiency (Manya et al ., 2002; Trinchese et al ., 2008). BDA‐410 strongly and reversibly inhibits cysteine proteases but not serine or aspartic proteinases.…”

Rho/ROCK pathway inhibition by CDK inhibitor p27kip1 participates in the onset of macrophage 3D-mesenchymal migration

“…Indeed, we have clearly shown that ROCK inhibition completely abolishes macrophage migration through fibrillar collagen. One explanation could be that -in contrast to tumour cells such as HT1080, which can employ mesenchymal migration in either loose or dense matrices (Carragher, 2006;Friedl and Wolf, 2003) -amoeboid migration is the default migration mode of macrophages in fibrillar collagen, whereas mesenchymal migration is only triggered by the contact of macrophages with dense matrices and could require additional effectors that are not expressed during amoeboid migration or upon macrophage contact with loose matrices. So, although ROCK inhibition induces an elongated macrophage morphology, this is not sufficient to trigger macrophage mesenchymal migration in fibrillar collagen.…”

Cytosolic HMGB1 controls the cellular autophagy/apoptosis checkpoint during inflammation

“…Instead, caspase 1-mediated activation of calpains in the absence of HMGB1 led to the inflammation and apoptosis seen in this model. Calpain activation does not degrade target proteins but rather cleaves them into stable fragments with functions that are different from the parent protein (37). The calpain proteases are ubiquitously expressed and play roles in cell division, cell movement, signal transduction, and apoptotic pathways (26).…”