Publications & Reports

Tripeptide analogues of MG132 as protease inhibitors.

Pehere AD, Nguyen S, Garlick SK, Wilson DW, Hudson I, Sykes MJ, Morton JD, Abell AD
Department of Chemistry, and Centre for Nanoscale BioPhotonics (CNBP), University of Adelaide, Adelaide, South Australia 5005, Australia. Electronic address: adpehere@mdanderson.org.

Abstract

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.

Link to publisher’s web site

Publication

  • Journal: Bioorganic & Medicinal Chemistry
  • Published: 01/01/2019
  • Volume: Epub ahead of print