jm8b00418_si_001.pdf (1.98 MB)
Stabilized β‑Hairpin Peptide Inhibits Insulin Degrading Enzyme
journal contribution
posted on 2018-08-27, 00:00 authored by 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 LiInsulin-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.