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

Hirofumi Noguchi, Chika Miyagi-Shiohira, Yoshiki Nakashima, Issei Saitoh, Masami Watanabe

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)1296-1308
Number of pages13
JournalAmerican Journal of Transplantation
Volume20
Issue number5
DOIs
Publication statusPublished - May 1 2020

Keywords

  • basic (laboratory) research/science
  • cell death: apoptosis
  • islet isolation
  • islet transplantation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

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