Chimeric peptide EP45 as a dual agonist at GLP-1 and NPY2R receptors

Oleg G. Chepurny, Ron L. Bonaccorso, Colin A. Leech, Torsten Wöllert, George M. Langford, Frank Schwede, Christian L. Roth, Robert P. Doyle, George G. Holz

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

We report the design and target validation of chimeric peptide EP45, a novel 45 amino acid monomeric dual agonist peptide that contains amino acid sequence motifs present within the blood glucose-lowering agent exendin-4 (Ex-4) and the appetite-suppressing agent PYY(3-36). In a new high-throughput FRET assay that provides real-time kinetic information concerning levels of cAMP in living cells, EP45 recapitulates the action of Ex-4 to stimulate cAMP production via the glucagon-like peptide-1 receptor (GLP-1R), while also recapitulating the action of PYY(3-36) to inhibit cAMP production via the neuropeptide Y2 receptor (NPY2R). EP45 fails to activate glucagon or GIP receptors, whereas for cells that co-express NPY2R and adenosine A2B receptors, EP45 acts in an NPY2R-mediated manner to suppress stimulatory effects of adenosine on cAMP production. Collectively, such findings are remarkable in that they suggest a new strategy in which the co-existing metabolic disorders of type 2 diabetes and obesity will be treatable using a single peptide such as EP45 that lowers levels of blood glucose by virtue of its GLP-1R-mediated effect, while simultaneously suppressing appetite by virtue of its NPY2R-mediated effect.

Original languageEnglish (US)
Article number3749
JournalScientific reports
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018

ASJC Scopus subject areas

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    Chepurny, O. G., Bonaccorso, R. L., Leech, C. A., Wöllert, T., Langford, G. M., Schwede, F., Roth, C. L., Doyle, R. P., & Holz, G. G. (2018). Chimeric peptide EP45 as a dual agonist at GLP-1 and NPY2R receptors. Scientific reports, 8(1), [3749]. https://doi.org/10.1038/s41598-018-22106-1