Tripeptide analogues of MG132 as protease inhibitors

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dc.contributor.authorPehere, A.D.
dc.contributor.authorNguyen, S.
dc.contributor.authorGarlick, S.K.
dc.contributor.authorWilson, D.W.
dc.contributor.authorHudson, I.
dc.contributor.authorSykes, M.J.
dc.contributor.authorMorton, J.D.
dc.contributor.authorAbell, A.D.
dc.date.issued2019
dc.description.abstractThe 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.
dc.description.statementofresponsibilityAshok D. Pehere, Steven Nguyen, Sarah K. Garlick, Danny W. Wilson, Irene Hudson, Matthew J. Sykes, James D. Morton, Andrew D. Abell
dc.identifier.citationBioorganic and Medicinal Chemistry, 2019; 27(2):436-441
dc.identifier.doi10.1016/j.bmc.2018.12.022
dc.identifier.issn0968-0896
dc.identifier.issn1464-3391
dc.identifier.orcidWilson, D.W. [0000-0002-5073-1405]
dc.identifier.orcidAbell, A.D. [0000-0002-0604-2629]
dc.identifier.urihttp://hdl.handle.net/2440/118429
dc.language.isoen
dc.publisherElsevier
dc.relation.grantARC
dc.rights© 2018 Elsevier Ltd. All rights reserved.
dc.source.urihttps://doi.org/10.1016/j.bmc.2018.12.022
dc.subjectCalpain inhibitors; 26S proteasome inhibitors; peptidomimetics; medicinal chemistry
dc.titleTripeptide analogues of MG132 as protease inhibitors
dc.typeJournal article
pubs.publication-statusPublished

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