A survey of Calpain Inhibitors
Abstract:Calpain is unique among the cysteine protease family of enzymes in that it combines thiol protease activity with calmodulin-like activity. Despite its wide spread distribution the exact physiological function(s) of calpain is yet to be deciphered. The enzyme is however, implicated in a number of pathophysiological conditions. Due to the potential of calpain as a therapeutic target a number of inhibitors have been described for the enzyme. In this article we have grouped calpain inhibitors into those derived from natural sources, and those derived from chemical synthesis. Additionally, an overview of functional groups that have been used as “warheads” of calpain inhibitors is presented along with a discussion of the structure activity relationship studies of the address region of peptidyl calpain inhibitors. Recent work in this area has led to a better understanding of the structural requirements for tight binding of inhibitors to the active site of calpain. A discussion of peptidomimetic calpain inhibitors, nonpeptide calpain inhibitors, and selectivity of some calpain inhibitors are also presented. The recent disclosure of the crystal structure of a nonpeptide calpain inhibitor bound to a hydrophobic pocket on the calcium-binding domain of calpain has opened the door to future development of potent cell permeable nonpeptide calpain inhibitors.
Keywords: Alzheimers disease; Calpain I; Calpain II(m Calpain); Calpain Inhibitor Warheads; Calpain Inhibitors; Calpastatin; Damnacanthal; EGF receptor; Morinda citrifolia; Non peptide Calpain Inhibitors; Peptidomimetic Calpain Inhibitor; Reversible and irreversible Calpain Inhibitor; Signal transduction; Structure activity relationship (sar); Thiol protease activity; arthritis and cataract; parkinsons disease; penicillide; spectrine Map 2; subarachnoid hemorrhage; thrombotic platelet aggregation
Document Type: Review Article
Publication date: 2000-12-01
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