From Venom-to-Vial-to-Pill: The Translational Journey of GLP-1 Peptides and the Evolving Landscape of Biopharmaceutics Modeling.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have become an important therapeutic option for metabolic disorders. Their development, from the early identification of exendin-4 in Gila-monster venom to the creation of long-acting analogues and the first oral peptide, marks a significant step in translational drug design. Each generation resolved issues of enzymatic instability, rapid clearance, and low permeability. These gains stemmed from improvements in acylation, fusion-protein engineering, and sodium N-(8-[2-hydroxybenzoyl]amino)caprylate (SNAC)-enabled absorption. This review integrates molecular evolution, formulation advances, and biopharmaceutics modeling, including physiologically based biopharmaceutics modeling (PBBM), to illustrate emerging strategies shaping next-generation oral peptide therapeutics.