Identification and Optimization of a Novel Inhibitor of Mitochondrial Calpain 10

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2008 Dec 17

PMID 19072163

Citations 7

Authors

Kyle A Rasbach

David D Arrington

Sina Odejinmi

Chris Giguere

Craig C Beeson

Rick G Schnellmann

Affiliations

Soon will be listed here.

Abstract

Calpain 10 has been localized to the mitochondria and is a key mediator of Ca(2+) induced mitochondrial dysfunction. A peptide screen followed by a series of modifications identified the homodisulfide form of CYGAK (CYGAK)(2) as an inhibitor of calpain 10 while showing no inhibitory activity against calpain 1. Methylation or truncation of the N-terminal cysteine significantly reduced the inhibitory activity of (CYGAK)(2) and inhibition was reversed by reducing agents, suggesting that CYGAK forms a disulfide with a cysteine near the active site. Data suggests CYGAK may be a P' calpain inhibitor and may achieve its specificity through this mechanism. CYGAK inhibited calpain activity in intact mitochondria, renal cells, and hepatocytes, prevented Ca(2+) induced cleavage of NDUFV2, and blocked Ca(2+) induced state III dysfunction. (CYGAK)(2) is the first P' specific calpain inhibitor and will be a valuable tool to prevent Ca(2+) induced mitochondrial dysfunction and explore the function of calpain 10.

Citing Articles

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Calpain 10 homology modeling with CYGAK and increased lipophilicity leads to greater potency and efficacy in cells.

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