Tripeptide analogues of MG132 as protease inhibitors
Date
2019
Authors
Pehere, A.D.
Nguyen, S.
Garlick, S.K.
Wilson, D.W.
Hudson, I.
Sykes, M.J.
Morton, J.D.
Abell, A.D.
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Journal article
Citation
Bioorganic and Medicinal Chemistry, 2019; 27(2):436-441
Statement of Responsibility
Ashok D. Pehere, Steven Nguyen, Sarah K. Garlick, Danny W. Wilson, Irene Hudson, Matthew J. Sykes, James D. Morton, Andrew D. Abell
Conference Name
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.
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© 2018 Elsevier Ltd. All rights reserved.