A survey of calpain inhibitors

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 pat hophysiological conditions. Due to the potential of calpain as a therapeuti c 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 overv iew of functional groups that have been used as "warheads" of calpain inhib itors is presented along with a discussion of the structure activity relati onship studies of the address region of peptidyl calpain inhibitors. Recent work in this area has led to a better understanding of the structural requ irements for tight binding of inhibitors to the active site of calpain. A d iscussion of peptidomimetic calpain inhibitors, nonpeptide calpain inhibito rs, and selectivity of some calpain inhibitors are also presented. The rece nt disclosure of the crystal structure of a nonpeptide calpain inhibitor bo und to a hydrophobic pocket on the calcium-binding domain of calpain has op ened the door to future development of potent cell permeable nonpeptide cal pain inhibitors.