We recently synthesized EP45, a first-in-class monomeric peptide with dual agonist properties at the glucagon-like peptide receptor (GLP-1R) and neuropeptide Y2 receptor (Y2-R).1 The design of EP45 is such that the N-terminus is comprised of residues 1-33 of the Heloderma GLP-1R agonist Exendin-4 (Ex-4), whereas the C-terminus contains residues 24-36 of the Y2-R agonist Peptide Tyrosine-Tyrosine 3-36 (PYY3-36) that is a mammalian hormone and neurotransmitter (Fig. 1). Subsequently, a paper by a team at Novo Nordisk reported a series of monomeric GLP-1R/Y2-R dual agonist peptides in which the N-termini are comprised of residues found within the mammalian hormone GLP-1 rather than Ex-4, while retaining portions of PYY3-36 at the C-terminus. 2 Collectively, these studies have spurred interest in the possible use of such dual GLP-1R/Y2-R agonists as a new treatment for metabolic disorders such as diabetes and obesity. For comparative purposes, the team at Novo Nordisk attempted to resynthesize the original EP45, thereby deriving a peptide designated as peptide 22. 2 Surprisingly, 22 exhibited high-affinity binding to the GLP-1R, but not to Y2-R. Thus, the team at Novo Nordisk concluded that EP45 is not an authentic GLP-1R/Y2-R dual agonist. However, we noted that the amino acid sequence of 22 is mistakenly not EP45, an error that is confirmed by the mass spectroscopy analysis presented by Novo. 2 Specifically, peptide 22 does not include Serine residue 11 (Ser11) of EP45, and for this reason it is instead a deletion product of such (Fig. 1). Thus, the prior findings obtained using peptide 22 cannot be construed to indicate that EP45 lacks dual GLP-1R/Y2-R agonist action. Here, we address this confusion in the published literature by expanding our analysis of EP45, thereby validating that it is truly a dual GLP-1R/Y2-R agonist. We also report new findings obtained using the EP45 structurally related peptides GEP44 and GEP44-W38 that are also validated to be authentic GLP-1R/Y2-R dual agonists (Fig. 1). To this end, we evaluate the receptor-binding properties of these peptides and further explore and re-validate the dual receptor agonism that is measurable in live-cell assays of cAMP production.

Chimeric peptide dual agonism at GLP-1 and neuropeptide Y2 receptors

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