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 Patrick Doyle, George G. Holz

Research output: Contribution to journalArticle

2 Citations (Scopus)

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

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Glucagon-Like Peptide 1
Peptides
Appetite
Blood Glucose
Adenosine A2B Receptors
Glucagon Receptors
Amino Acid Motifs
Adenosine
Type 2 Diabetes Mellitus
Amino Acid Sequence
Obesity
Amino Acids
neuropeptide Y2 receptor
Glucagon-Like Peptide-1 Receptor
exenatide

ASJC Scopus subject areas

  • General

Cite this

Chepurny, O. G., Bonaccorso, R. L., Leech, C. A., Wöllert, T., Langford, G. M., Schwede, F., ... 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

Chimeric peptide EP45 as a dual agonist at GLP-1 and NPY2R receptors. / Chepurny, Oleg G.; Bonaccorso, Ron L.; Leech, Colin A.; Wöllert, Torsten; Langford, George M; Schwede, Frank; Roth, Christian L.; Doyle, Robert Patrick; Holz, George G.

In: Scientific Reports, Vol. 8, No. 1, 3749, 01.12.2018.

Research output: Contribution to journalArticle

Chepurny, OG, Bonaccorso, RL, Leech, CA, Wöllert, T, Langford, GM, Schwede, F, Roth, CL, Doyle, RP & Holz, GG 2018, 'Chimeric peptide EP45 as a dual agonist at GLP-1 and NPY2R receptors', Scientific Reports, vol. 8, no. 1, 3749. https://doi.org/10.1038/s41598-018-22106-1
Chepurny OG, Bonaccorso RL, Leech CA, Wöllert T, Langford GM, Schwede F et al. Chimeric peptide EP45 as a dual agonist at GLP-1 and NPY2R receptors. Scientific Reports. 2018 Dec 1;8(1). 3749. https://doi.org/10.1038/s41598-018-22106-1
Chepurny, Oleg G. ; Bonaccorso, Ron L. ; Leech, Colin A. ; Wöllert, Torsten ; Langford, George M ; Schwede, Frank ; Roth, Christian L. ; Doyle, Robert Patrick ; Holz, George G. / Chimeric peptide EP45 as a dual agonist at GLP-1 and NPY2R receptors. In: Scientific Reports. 2018 ; Vol. 8, No. 1.
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