Calpains are non-lysosomal neutral cysteine proteinases found in almost all eukaryotes and a few bacteria. The enzymes require calcium ions for activation and consist of 15 isoforms of which calpain-1 (<i>μ</i>-calpain) and calpain-2 (m-calpain) are ubiquitously expressed in mammalian cells and are the most studied calpain isoforms. The enzymes modulate cell physiology by catalyzing the limited proteolysis of target substrates which include regulatory proteins, cytoskeletal proteins, muscle proteins, proteins in mitosis, and several others. They participate in several normal cellular events such as cytoskeletal remodeling and cell motility, cell function, signal transduction pathways, apoptosis, regulation of the cell cycle. The cellular actions of calpains are tightly regulated by calpastatin, which is the specific intracellular inhibitor of the enzymes. Deregulation of calpain action has been implicated in a variety of diseases and elevated levels of the enzyme have been measured in various pathophysiolgical conditions including neurological disorders (Alzheimer’s, Huntington’s, Parkinson’s disease and multiple sclerosis), stroke, ischemic and traumatic brain injury, cataract, cancer, muscular dystrophies, diabetes, inflammation, and human immunodeficiency virus disorders. The implication of calpains in pathological events has led to the postulation that calpain inhibitors may be useful in treating human disease. This has inspired the discovery calpain inhibitors as potential therapeutic agents. The poster provides an overview of selected calpain inhibitors that have been disclosed in the patent and scientific literature over the past decade along with a discussion of the preclinical and clinical trials outcomes of the inhibitors.

Calpain inhibitors: Molecules in search of a therapeutic home

ACS Spring Meeting 2021

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