Tripeptide analogues of MG132 as protease inhibitors.


Department of Chemistry, and Centre for Nanoscale BioPhotonics (CNBP), University of Adelaide, Adelaide, South Australia 5005, Australia. Electronic address: [Email]


The 26S proteasome and calpain are linked to a number of important human diseases. Here, we report a series of analogues of the prototypical tripeptide aldehyde inhibitor MG132 that show a unique combination of high activity and selectivity for calpains over proteasome. Tripeptide aldehydes (1-3) with an aromatic P3 substituent show enhanced activity and selectivity against ovine calpain 2 relative to chymotrypsin-like activity of proteasome. Docking studies reveal the key contacts between inhibitors and calpain to confirm the importance of the S3 pocket with respect to selectivity between calpains 1 and 2 and the proteasome.


26S proteasome inhibitors,Calpain inhibitors,Medicinal chemistry,Peptidomimetics,