A new cell-permeable calpain inhibitor.

The ubiquitous calpains, mu- and m-calpain, are implicated in a variety of vital (patho)physiological processes and therefore cell-permeable specific inhibitors represent important tools for defining the role of calpains in cells and animal models. A synthetic N-acetylated 27-mer peptide derived from exon B of the human calpastatin inhibitory domain 1 is known to be the most potent and selective reversible inhibitor of calpains. To improve the membrane permeability of this peptidic inhibitor, it was N-terminally extended with or disulfide-linked to the C-terminal 7-mer fragment of penetratin, a well-established vector for cell membrane translocation of bioactive compounds. Despite the shorter penetratin sequence, both constructs showed increased cell permeability and retained their full calpain inhibitory potency.