Developments in the design and synthesis of calpain inhibitors

Abstract

Calpains are Ca(2+)-dependent cysteine proteases that play an important role in cell differentiation and in apoptosis/necrosis. The overactivation of calpain is connected with a number of diseases, including cataracts and traumatic brain injury, making calpain an attractive drug target. The development of selective inhibitors of calpain has, however, proved difficult, due to a lack of detailed structural information on the protein. This difficulty has been somewhat alleviated with recent reports on the X-ray crystal structures of engineered calpains and improved biochemical characterization of the protein. This review describes properties and X-ray crystal structures of calpain, and the synthesis and binding affinities of novel calpain inhibitors.