α/Sulfono-γ-AA peptide hybrids agonist of GLP-1R with prolonged action both in vitro and in vivo.

Yan Shi; Candy Lee; Peng Sang; Zaid Amso; David Huang; Weixia Zhong; Meng GU; Lulu Wei; Vân T B Nguyen-tran; Jingyao Zhang; Weijun Shen; Jianfeng Cai

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α/Sulfono-γ-AA peptide hybrids agonist of GLP-1R with prolonged action both in vitro and in vivo.

Author: Yan SHI ¹ ; Candy LEE ² ; Peng SANG ¹ ; Zaid AMSO ² ; David HUANG ² ; Weixia ZHONG ² ; Meng GU ¹ ; Lulu WEI ¹ ; Vân T B NGUYEN-TRAN ² ; Jingyao ZHANG ¹ ; Weijun SHEN ² ; Jianfeng CAI ¹
Author Information

1. Department of Chemistry, University of South Florida, Tampa, FL 33620, USA.
2. Calibr at Scripps Research, La Jolla, CA 92037, USA.
Publication Type:Journal Article
Keywords: GLP-1; GLP-1R agonists; Helical structures; Peptidomimetics; Pharmacological activity; Rational design; Stability; Type-2 diabetes treatments
From: Acta Pharmaceutica Sinica B 2023;13(4):1648-1659
CountryChina
Language:English
Abstract: Peptides are increasingly important resources for biological and therapeutic development, however, their intrinsic susceptibility to proteolytic degradation represents a big hurdle. As a natural agonist for GLP-1R, glucagon-like peptide 1 (GLP-1) is of significant clinical interest for the treatment of type-2 diabetes mellitus, but its in vivo instability and short half-life have largely prevented its therapeutic application. Here, we describe the rational design of a series of α/sulfono-γ-AA peptide hybrid analogues of GLP-1 as the GLP-1R agonists. Certain GLP-1 hybrid analogues exhibited enhanced stability (t _1/2 > 14 days) compared to t _1/2 (<1 day) of GLP-1 in the blood plasma and in vivo. These newly developed peptide hybrids may be viable alternative of semaglutide for type-2 diabetes treatment. Additionally, our findings suggest that sulfono-γ-AA residues could be adopted to substitute canonical amino acids residues to improve the pharmacological activity of peptide-based drugs.