Design of Potent and Proteolytically Stable Biaryl-Stapled GLP-1R/GIPR Peptide Dual Agonists
| Autor: | Yifang Yang, Candy Lee, Reddy Rajasekhar Reddy, David J. Huang, Weixia Zhong, Vân T. B. Nguyen-Tran, Weijun Shen, Qing Lin |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | ACS Chem Biol |
| ISSN: | 1554-8937 1554-8929 |
| Popis: | Recent clinical trials have revealed that the chimeric peptide hormones simultaneously activating glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) demonstrate superior efficacy in glycemic control and body weight reduction, better than those activating the GLP-1R alone. However, the linear peptide-based GLP-1R/GIPR dual agonists are susceptible to proteolytic cleavage by common digestive enzymes present in the gastrointestinal tract and thus not suitable for oral administration. Here, we report the design and synthesis of biaryl-stapled peptides, with and without fatty diacid attachment, that showed potent GLP-1R/GIPR dual agonist activities. Compared to a linear peptide dual agonist and semaglutide, the biaryl-stapled peptides displayed drastically improved proteolytic stability against the common digestive enzymes. Furthermore, two stapled peptides showed excellent efficacy in an oral glucose tolerance test in mice, owing to their potent receptor activity in vitro and good pharmacokinetics exposure upon subcutaneous injection. By exploring a more comprehensive set of biaryl staplers, we expect that this stapling method could facilitate the design of the stapled peptide-based dual agonists suitable for oral administration. |
| Databáze: | OpenAIRE |
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