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 itsinstability and short half-life have largely prevented its therapeutic application. Here, we describe the rational design of a series of/sulfono--AA peptide hybrid analogues of GLP-1 as the GLP-1R agonists. Certain GLP-1 hybrid analogues exhibited enhanced stability ( > 14 days) compared to(<1 day) of GLP-1 in the blood plasma and. These newly developed peptide hybrids may be viable alternative of semaglutide for type-2 diabetes treatment. Additionally, our findings suggest that sulfono--AA residues could be adopted to substitute canonical amino acids residues to improve the pharmacological activity of peptide-based drugs.