Peptide Marriages: Modular Assembly of Multi‐Agonist Therapeutics

ABSTRACT Multi‐receptor peptide agonists represent an effective strategy for obesity treatment, extending the success of incretin‐based therapies through simultaneous engagement of complementary targets. Their development, however, is synthetically demanding, as each receptor combination typically requires de novo preparation of large fusion peptides. We report a modular polyethylene glycol (PEG)‐based scaffold that enables orthogonal attachment of up to three functional components, including therapeutic peptides, half‐life–extending units, and other labels, via sequential strain‐promoted azide–alkyne cycloaddition (SPAAC) and copper‐catalysed azide–alkyne cycloaddition (CuAAC). The scaffold is assembled on solid phase without intermediate purification, providing a readily accessible and versatile linker. Using glucagon‐like peptide‐1 (GLP‐1) and amylin receptor agonists as a proof‐of‐concept, dual‐agonist constructs with tuneable valency and functionality were rapidly generated. Lead conjugates displayed balanced, low‐picomolar potency at both receptors in cyclic adenosine monophosphate (cAMP) assays and showed selective receptor‐mediated internalisation in GLP‐1 receptor‐expressing cells. This orthogonal click‐based platform enables rapid and modular multi‐agonist assembly, facilitating systematic exploration of receptor combinations, valency, and payload effects. Beyond incretin biology, it offers a general route to multifunctional peptide therapeutics and diagnostics.