Design, synthesis, and evaluation of novel irreversible inhibitors for caspases

New classes of irreversible inhibitors have been developed targeting caspases (cysteinyl aspartate specific protease), which are the key mediators of apoptosis (programmed cell death, cell suicide). Aza-peptide epoxides and aza-peptide Michael acceptors with an aza-Asp residue at the P1 position have been designed and synthesized as potential inhibitors for caspases. The kinetic measurements with aza-peptide epoxides and aza-peptide Michael acceptors demonstrated that these inhibitors were potent and specific inactivators for caspases. The second order inhibition rate constants are in the order of 106 M−1s−1. Furthermore, these novel classes of inhibitors were highly specific for clan CD cysteine proteases. Aza-peptide epoxides and aza-peptide Michael acceptors designed with caspase specific sequences do not show any cross reactivity with clan CA cysteine proteases such as papain, cathepsin B, and calpain. Caspase specific aza-peptide epoxides and aza-peptide Michael acceptors could lead to the development of potential drugs, where caspases are recognized as novel therapeutic targets for neurodegenerative diseases such as stroke, ALS, Huntington's disease, Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Aza-peptide epoxides and aza-peptide Michael acceptors designed for caspases would also be invaluable in elucidating the roles of individual caspases in inflammatory pathways and biochemical processes such as apoptosis.