Name: Shubhendu Palei
Diploma / M.Sc degree: IIT Kanpur, India
(June 2012)

PhD Project: Designing Novel Caspase-3 inhibitor

Abstract of Research Project

Caspases or cysteine-aspartic proteases are a family of cysteine proteases that play an important role in apoptosis, necrosis and inflammation. Caspase-3 is an effector Caspase which cleaves the protein substrates to trigger the apoptosis cascade inside the cell. Caspase-3 targets more than 800 proteins in the cell and is one of the vital proteases responsible for cellular degradation during apoptosis. The active sites of Caspases have absolute requirement of Aspartic acid (D) residue at S1 subsite and at least four amino acids upstream of the cleavage site. The three dimensional crystal structures of Caspases suggest that these enzymes employ a Cysteine protease mechanism involving a catalytic dyad of Cys and His. Many peptide based inhibitors have been identified based on the active site reactivity and proved successful in inhibiting other Cysteine proteases also. Several groups like aldehydes, nitriles, ketones at P1 residue of the inhibitor have been shown to be potent reversible inhibitors of Cysteine proteases. But till now they have not been successful in clinical trials because of the cross reactivity with other nucleophiles in the living cell. Therefore we plan to develop an inhibitor having a reactive group at the C terminus with high substrate specificity and less cross reactivity. The design of such inhibitors might add a new dimension to caspase-3 inhibition.