alpha/Sulfono-gamma-AA peptide hybrids agonist of GLP-1R with prolonged action both in vitro and in vivo

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 thera-peutic application. Here, we describe the rational design of a series of a/sulfono-7-AA peptide hybrid analogues of GLP-1 as the GLP-1R agonists. Certain GLP-1 hybrid analogues exhibited enhanced stabil-ity (t1/2 > 14 days) compared to t1/2 (<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. Addi-tionally, our findings suggest that sulfono-7-AA residues could be adopted to substitute canonical amino acids residues to improve the pharmacological activity of peptide-based drugs.(c) 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).