On December 5, 2017, the U.S. FDA approved Novo Nordisk A/S's diabetes drug Ozempic, whose active ingredient, semaglutide, represents a major advancement in the class of glucagon-like peptide-1 (GLP-1) analogues. These analogues mimic the action of an intestinal hormone that promotes insulin secretion, thereby playing a pivotal role in metabolic regulation. Since then, semaglutide has profoundly transformed the treatment landscape for type 2 diabetes and obesity, demonstrating efficacy in glycemic control, weight management and cardiovascular risk mitigation. Yet, it remains an open question whether semaglutide is the best GLP-1 receptor (GLP-1R) agonist either as of now or in future. Given GLP-1R as the therapeutic target, a structural basis of the GLP-1-GLP-1R interaction is paramount for the design of GLP-1 analogues that fully harness the therapeutic potential of GLP-1R activation. Thus, this study employs a structural biophysical approach to enhance GLP-1R activation through the rational design of semaglutide analogues. By incorporating an electrostatic scaffold of interfacial salt bridges, site-specific missense mutations were engineered into the semaglutide backbone to establish additional stabilizing interactions with the extracellular domain (ECD) of GLP-1R, thereby enhancing ligand-receptor binding and activation. In addition to 564 semaglutide analogues, the structural biophysical analysis here also reveal the presence of an electrostatic scaffold comprising four salt bridges at the semaglutide-GLP-1R binding interface. Drawing parallels with the continued optimization of insulin analogues, this articles proposes that the electrostatic scaffold offers a robust framework for the continued development of next-generation GLP-1R agonists, enabling more precise and effective therapies for managing metabolic diseases.