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|Title:||Tripeptide analogues of MG132 as protease inhibitors|
|Citation:||Bioorganic and Medicinal Chemistry, 2019; 27(2):436-441|
|Ashok D. Pehere, Steven Nguyen, Sarah K. Garlick, Danny W. Wilson, Irene Hudson, Matthew J. Sykes, James D. Morton, Andrew D. Abell|
|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.|
|Keywords:||Calpain inhibitors; 26S proteasome inhibitors; peptidomimetics; medicinal chemistry|
|Rights:||© 2018 Elsevier Ltd. All rights reserved.|
|Appears in Collections:||Biochemistry publications|
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