Premium
Novel cell‐permeable p38‐MAPK inhibitor efficiently prevents porcine islet apoptosis and improves islet graft function
Author(s) -
Noguchi Hirofumi,
MiyagiShiohira Chika,
Nakashima Yoshiki,
Saitoh Issei,
Watanabe Masami
Publication year - 2020
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.15740
Subject(s) - islet , p38 mitogen activated protein kinases , transplantation , apoptosis , mapk/erk pathway , microbiology and biotechnology , kinase , mitogen activated protein kinase , protein kinase a , peptide , medicine , biology , pharmacology , cancer research , biochemistry , endocrinology , diabetes mellitus
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‐p38I 110 significantly inhibited the activation of p38. To evaluate the effects of 11R‐p38I 110 , porcine islets were incubated with 10 µmol/L 11R‐p38I 110 or a mutant form designated 11R‐mp38I 110 . After islet transplantation, blood glucose levels reached the normoglycemic range in 58.3% and 0% of diabetic mice treated with 11R‐p38I 110 or 11R‐mp38I 110 , respectively. These data suggest that 11R‐p38I 110 inhibited islet apoptosis and improved islet function. Peptide p38I 110 is a noncompetitive inhibitor of ATP and targets a unique docking site. Therefore, 11R‐p38I 110 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.