Identification and optimization of a novel inhibitor of mitochondrial calpain 10

Kyle A. Rasbach, David D. Arrington, Sina Odejinmi, Chris Giguere, Craig C. Beeson, Rick G. Schnellmann

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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 Ṕ 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 Ṕ specific calpain inhibitor and will be a valuable tool to prevent Ca 2+ induced mitochondrial dysfunction and explore the function of calpain 10.

Original languageEnglish (US)
Pages (from-to)181-188
Number of pages8
JournalJournal of Medicinal Chemistry
Volume52
Issue number1
DOIs
StatePublished - Jan 8 2009
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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