Stabilized β-Hairpin Peptide Inhibits Insulin Degrading Enzyme

Journal of Medicinal Chemistry
Dan YangZigang Li

Abstract

Insulin-degrading enzyme (IDE) plays a critical role in both the proteolytic degradation and inactivation of insulin. The exploration of novel IDE inhibitors could aid in the study of novel therapeutics for type-2 diabetes. Herein, we report a hypothesized stabilized β-hairpin peptide that can efficiently inhibit the enzymatic activity of IDE. The resulting stabilized peptide B35 is demonstrated to activate the AKT phosphorylation pathway in skeletal muscle cells and is shown to slow insulin degradation. An 80 mg kg-1 intraperitoneal (i.p.) injection of the stabilized β-hairpin peptide B35 is demonstrated to improve glucose tolerance during an oral glucose tolerance test in obese mouse model. We note that this stabilized peptide exhibited negligible cytotoxicity in both in vitro and in vivo assays, even at high concentrations (300 μM). This study suggests that IDE peptide inhibitors could function as potentially meaningful candidates for the development of type-2 diabetes therapeutics.

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Citations

Mar 7, 2021·International Journal of Molecular Sciences·Malcolm A LeissringGermán Perdomo
Apr 10, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Yuval NashDan Frenkel
Aug 17, 2021·The Journal of Pathology·Luís SousaHugo Vicente Miranda

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