Stabilized β‑Hairpin Peptide Inhibits Insulin Degrading Enzyme Dan Yang Weirong Qin Xiaodong Shi Bili Zhu Mingsheng Xie Hui Zhao Bin Teng Yujie Wu Rongtong Zhao Feng Yin Peigen Ren Lizhong Liu Zigang Li 10.1021/acs.jmedchem.8b00418.s001 https://acs.figshare.com/articles/journal_contribution/Stabilized_Hairpin_Peptide_Inhibits_Insulin_Degrading_Enzyme/7056524 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 <b>B35</b> is demonstrated to activate the AKT phosphorylation pathway in skeletal muscle cells and is shown to slow insulin degradation. An 80 mg kg<sup>–1</sup> intraperitoneal (i.p.) injection of the stabilized β-hairpin peptide <b>B35</b> 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 <i>in vitro</i> and <i>in vivo</i> 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. 2018-08-27 00:00:00 type -2 diabetes therapeutics insulin degradation IDE peptide inhibitors β- hairpin peptide type -2 diabetes β- hairpin peptide B 35 novel IDE inhibitors vivo assays muscle cells peptide B 35 glucose tolerance test AKT phosphorylation pathway glucose tolerance novel therapeutics mouse model