van der Velden_2026_Biomed.J__101037

Glucagon-like peptide-1 (GLP-1) analogs exert potent metabolic effects through structural features that govern receptor engagement, signaling, and pharmacokinetics. Key structural determinants include N-terminal modifications that confer resistance to dipeptidyl peptidase-4 degradation, as well as C-terminal and backbone elements that stabilize peptide helicity and enhance GLP-1 receptor affinity. Lipidation and albumin-binding strategies prolong systemic exposure by increasing circulating half-life, forming the basis of long-acting agents such as liraglutide and semaglutide. Structural variation further modulates signaling bias between G protein pathways and beta-arrestin recruitment, potentially influencing therapeutic efficacy. Emerging multi-receptor agonists extend these principles across incretin receptor families and are increasingly supported by computational approaches to peptide optimization. Collectively, these advances illustrate how rational design drives the development of next-generation incretin therapeutics. This review synthesizes current insights into structural determinants of GLP-1 analogs and highlights future directions in the field.