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:
26S proteasome inhibitors; Calpain inhibitors; Medicinal chemistry; Peptidomimetics.
Copyright © 2018 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antimalarials / chemical synthesis
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Antimalarials / chemistry
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Antimalarials / pharmacology
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Calpain / chemistry
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Catalytic Domain
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Cysteine Proteinase Inhibitors / chemical synthesis
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Cysteine Proteinase Inhibitors / chemistry
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Cysteine Proteinase Inhibitors / pharmacology*
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Leupeptins / chemical synthesis
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Leupeptins / chemistry
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Leupeptins / pharmacology*
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Molecular Docking Simulation
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Molecular Structure
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Plasmodium falciparum / enzymology
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Proteasome Endopeptidase Complex / chemistry
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Proteasome Inhibitors / chemical synthesis
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Proteasome Inhibitors / chemistry
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Proteasome Inhibitors / pharmacology*
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Protein Conformation
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Rats
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Sheep
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Swine
Substances
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Antimalarials
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Cysteine Proteinase Inhibitors
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Leupeptins
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Proteasome Inhibitors
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Calpain
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Proteasome Endopeptidase Complex
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ATP dependent 26S protease
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde