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Calpain 10 is a ubiquitously expressed mitochondrial and cytosolic Ca(2+)-regulated cysteine protease in which overexpression or knockdown leads to mitochondrial dysfunction and cell death. We previously identified a potent and specific calpain 10 peptide inhibitor (CYGAK), but it was not efficacious in cells. Therefore, we created a homology model using the calpain 10 amino acid sequence and calpain 1 3-D structure and docked CYGAK in the active site. Using this model we modified the inhibitor to improve potency 2-fold (CYGAbuK). To increase cellular efficacy, we created CYGAK-S-phenyl-oleic acid heterodimers. Using renal mitochondrial matrix CYGAK, CYGAK-OC, and CYGAK-ON had IC(50)'s of 70, 90, and 875 nM, respectively. Using isolated whole renal mitochondria CYGAK, CYGAK-OC, and CYGAK-ON had IC(50)'s of 95, 196, and &gt;10,000 nM, respectively. Using renal proximal tubular cells (RPTC) in primary culture, 30 min exposures to CYGAK-OC and CYGAbuK-OC decreased cellular calpain activity approximately 20% at 1 μM, and concentrations up to 100 μM had no additional effect. RPTC treated with 10 μM CYGAK-OC for 24 h induced accumulation of ATP synthase β and NDUFB8, two calpain 10 substrates. In summary, we used molecular modeling to improve the potency of CYGAK, while creating CYGAK-oleic acid heterodimers to improve efficacy in cells. Since calpain 10 has been implicated in type 2 diabetes and renal aging, the use of this inhibitor may contribute to elucidating the role of calpain 10 in these and other diseases.

Calpain 10 Homology Modeling with CYGAK and Increased Lipophilicity Leads to Greater Potency and Efficacy in Cells