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 language | English (US) |
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Pages (from-to) | 181-188 |
Number of pages | 8 |
Journal | Journal of Medicinal Chemistry |
Volume | 52 |
Issue number | 1 |
DOIs | |
State | Published - Jan 8 2009 |
Externally published | Yes |
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery