Novel cell-permeable p38-MAPK inhibitor efficiently prevents porcine islet apoptosis and improves islet graft function

During islet transplantation, mitogen-activated protein kinase (MAPK) p38 is preferentially activated in response to the isolation of islets and the associated inflammation. Although therapeutic effects of p38 inhibitors are expected, the clinical application of small-molecule inhibitors of p38 is not recommended because of their serious adverse effects on the liver and central nervous system. Here we designed peptides to inhibit p38, which were derived from the sites on p38 that mediate binding to proteins such as MAPK kinases. Peptide 11R-p38I₁₁₀ significantly inhibited the activation of p38. To evaluate the effects of 11R-p38I₁₁₀, porcine islets were incubated with 10 µmol/L 11R-p38I₁₁₀ or a mutant form designated 11R-mp38I₁₁₀. After islet transplantation, blood glucose levels reached the normoglycemic range in 58.3% and 0% of diabetic mice treated with 11R-p38I₁₁₀ or 11R-mp38I₁₁₀, respectively. These data suggest that 11R-p38I₁₁₀ inhibited islet apoptosis and improved islet function. Peptide p38I₁₁₀ is a noncompetitive inhibitor of ATP and targets a unique docking site. Therefore, 11R-p38I₁₁₀ specifically inhibits p38 activation, which may avoid the adverse effects that have discouraged the clinical use of small-molecule inhibitors of p38. Moreover, our methodology to design “peptide inhibitors” could be used to design other inhibitors derived from the binding sites of proteins.