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Synthetic pentapeptides inhibiting autophosphorylation of insulin receptor in a non‐ATP‐competitive mechanism
Author(s) -
Kato Masaki,
Abe Mineo,
Kuroda Yoshihiro,
Hirose Munetaka,
Nakano Minoru,
Handa Tetsurou
Publication year - 2009
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.1114
Subject(s) - autophosphorylation , mechanism (biology) , chemistry , insulin receptor , receptor , insulin , pharmacology , microbiology and biotechnology , biochemistry , biology , phosphorylation , endocrinology , insulin resistance , protein kinase a , philosophy , epistemology
In an attempt to develop non‐ATP‐competitive inhibitors of the autophosphorylation of IR, the effects of the synthetic peptides, Ac‐DIY 1158 ET‐NH 2 and Ac‐DY 1162 Y 1163 RK‐NH 2 , on the phosphorylation of IR were studied in vitro . The peptides were derived from the amino‐acid sequence in the activation loop of IR. They inhibited the autophosphorylation of IR to 20.5 and 40.7%, respectively, at 4000 µ M . The Asp/Asn‐ and Glu/Gln‐substituted peptides, Ac‐NIYQT‐NH 2 and Ac‐NYYRK‐NH 2 , more potently inhibited the autophosphorylation than did the corresponding parent peptides. The inhibitory potencies of the substituted peptides were decreased with increasing concentrations of ATP, indicating that these peptides employ an ATP‐competitive mechanism in inhibiting the autophosphorylation of IR. In contrast, those of the parent peptides were not affected. Mass spectrometry showed that the parent peptides were phosphorylated by IR, suggesting that they interact with the catalytic loop. Moreover, docking simulations predicted that the substituted peptides would interact with the ATP‐binding region of IR, whereas their parent peptides would interact with the catalytic loop of IR. Thus, Ac‐DIYET‐NH 2 and Ac‐DYYRK‐NH 2 are expected to be non‐ATP‐competitive inhibitors. These peptides could contribute to the development of a drug employing a novel mechanism. Copyright © 2009 European Peptide Society and John Wiley & Sons, Ltd.