Peptides that regulate glucose homeostasis and energy utilization have shown potential as new therapeutics for obesity and associated comorbidities such as cardiovascular disease and type II diabetes. Three hormones, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon (GCG), contribute independently to physiological effects valuable for body-weight reduction and metabolic control. Administration of GLP-1, GIP, and GCG simultaneously has shown body mass reduction in animal models. In an effort to combine all effects into one peptide, a monomeric triple agonist for GLP-1, GIP, and GCG receptors was found to exhibit benefits of metabolic regulation and reduced body weight in diet induced obese mice. What remains unknown is to what extent each receptor needs to be activated to achieve greatest loss in bodyweight and maintain “normoglycemia”. Here we present a single location on the N-terminus of the triple agonist that is tolerant to chemical modification and generates a handle for a diverse library of peptides to modulate receptor balance. This position was previously reported to be required for receptor activation, but we have found new chemical modifications that fine-tune potency and efficacy. We demonstrate modulation of potency for GLP-1, GIP, and GCG receptors by (1) N-terminal alkylation by reductive amination, (2) introduction of functional groups with a trivalent iodonium salt to modulate the pKa of the N-terminal amine, and (3) alteration of polarity, size, and polarizability of the first N-terminal amino acid side chain. Each modified triple agonist is tested individually for GLP-1, GIP, and GCG receptor potency and efficacy in a cellular luciferase reporter assay. We report a diverse library of multi-receptor agonists with N-terminal variations and EC50’s between 1 and 20-fold of native peptides. Finally, we show a diverse array of small N-terminal molecular modifications of one triple agonist peptide that can influence receptor potency and balance to lead to optimal bodyweight reduction and metabolic control.

Design of multi-receptor peptide agonists

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.