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

摘要

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 a/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.