A Hydrophobic Tag-Assisted Liquid-Phase Strategy for the Synthesis of Retatrutide

Retatrutide is a novel triple agonist that targets the glucagon receptor (GCGR), the glucose-dependent insulinotropic polypeptide receptor (GIPR), and the glucagon-like peptide-1 receptor (GLP-1R). At present, its synthesis relies predominantly on solid-phase peptide synthesis (SPPS), an approach that suffers from inherent limitations in terms of efficiency, scalability, and structural flexibility. In this study, we present a novel method for the synthesis of Retatrutide, namely hydrophobic tag-assisted liquid-phase peptide synthesis (LPPS). This method provides a practical and flexible alternative to conventional SPPS for the synthesis of Retatrutide.