Tripeptide analogues of MG132 as protease inhibitors. Issue 2 (15th January 2019)

• Record Type: Journal Article
• Authors: Pehere, Ashok D.; Nguyen, Steven; Garlick, Sarah K.; Wilson, Danny W.; Hudson, Irene; Sykes, Matthew J.; Morton, James D.; Abell, Andrew D.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 27:Issue 2(2019)
• Page Start: 436
• Page End: 441
• Publication Date: 2019-01-15
• Subjects: Calpain inhibitors -- 26S proteasome inhibitors -- Peptidomimetics -- Medicinal chemistry; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.12.022
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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.