Chimeric Peptide EP45 As a Dual Agonist at GLP-1 and NPY2R Receptors

Overview

Journal Sci Rep

Specialty Science

Date 2018 Mar 2

PMID 29491394

Citations 22

Authors

Oleg G Chepurny

Ron L Bonaccorso

Colin A Leech

Torsten Wollert

George M Langford

Frank Schwede

Christian L Roth

Robert P Doyle

George G Holz

Affiliations

Soon will be listed here.

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 Y receptor (NPY2R). EP45 fails to activate glucagon or GIP receptors, whereas for cells that co-express NPY2R and adenosine A 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.

Citing Articles

Photochemically-enabled, post-translational production of C-terminal amides.

Hymel D, Wojcik F, Halskov K, Hogendorf W, Wong S, Williams B Nat Commun. 2024; 15(1):7162.

PMID: 39616180 PMC: 11608224. DOI: 10.1038/s41467-024-51005-5.

Effects of systemic oxytocin and beta-3 receptor agonist (CL 316243) treatment on body weight and adiposity in male diet-induced obese rats.

Slattery J, Rambousek J, Tsui E, Honeycutt M, Goldberg M, Graham J bioRxiv. 2024; .

PMID: 39502365 PMC: 11537314. DOI: 10.1101/2024.09.27.615550.

The Brain-Heart Network of Syncope.

Barik S, Riddell T Int J Mol Sci. 2024; 25(13).

PMID: 39000068 PMC: 11241714. DOI: 10.3390/ijms25136959.

Molecular hybridization strategy for tuning bioactive peptide function.

Pedron C, Torres M, Oliveira C, Silva A, Andrade G, Wang Y Commun Biol. 2023; 6(1):1067.

PMID: 37857855 PMC: 10587126. DOI: 10.1038/s42003-023-05254-7.

Optimization of a Glucagon-Like Peptide 1 Receptor Antagonist Antibody for Treatment of Hyperinsulinism.

Peterson S, Juliana C, Hu C, Chai J, Holliday C, Chan K Diabetes. 2023; 72(9):1320-1329.

PMID: 37358194 PMC: 10450825. DOI: 10.2337/db22-1039.

References

Tatemoto K, Mutt V . Isolation of two novel candidate hormones using a chemical method for finding naturally occurring polypeptides. Nature. 1980; 285(5764):417-8. DOI: 10.1038/285417a0. View

Pedersen S, Sasikumar P, Chelur S, Holst B, Artmann A, Jensen K . Peptide hormone isoforms: N-terminally branched PYY3-36 isoforms give improved lipid and fat-cell metabolism in diet-induced obese mice. J Pept Sci. 2010; 16(11):664-73. DOI: 10.1002/psc.1281. View

Choudhury S, Tan T, Bloom S . Gastrointestinal hormones and their role in obesity. Curr Opin Endocrinol Diabetes Obes. 2015; 23(1):18-22. DOI: 10.1097/MED.0000000000000216. View

Murphy K, Dhillo W, Bloom S . Gut peptides in the regulation of food intake and energy homeostasis. Endocr Rev. 2006; 27(7):719-27. DOI: 10.1210/er.2006-0028. View

Holz G, Chepurny O . Glucagon-like peptide-1 synthetic analogs: new therapeutic agents for use in the treatment of diabetes mellitus. Curr Med Chem. 2003; 10(22):2471-83. PMC: 2911578. DOI: 10.2174/0929867033456648. View

Chepurny O, Leech C, Kelley G, Dzhura I, Dzhura E, Li X . Enhanced Rap1 activation and insulin secretagogue properties of an acetoxymethyl ester of an Epac-selective cyclic AMP analog in rat INS-1 cells: studies with 8-pCPT-2'-O-Me-cAMP-AM. J Biol Chem. 2009; 284(16):10728-36. PMC: 2667760. DOI: 10.1074/jbc.M900166200. View

Sohn J, Elmquist J, Williams K . Neuronal circuits that regulate feeding behavior and metabolism. Trends Neurosci. 2013; 36(9):504-12. PMC: 3769497. DOI: 10.1016/j.tins.2013.05.003. View

Chepurny O, Holz G . A novel cyclic adenosine monophosphate responsive luciferase reporter incorporating a nonpalindromic cyclic adenosine monophosphate response element provides optimal performance for use in G protein coupled receptor drug discovery efforts. J Biomol Screen. 2007; 12(5):740-6. PMC: 2919231. DOI: 10.1177/1087057107301856. View

Mustafa S, Nadeem A, Fan M, Zhong H, Belardinelli L, Zeng D . Effect of a specific and selective A(2B) adenosine receptor antagonist on adenosine agonist AMP and allergen-induced airway responsiveness and cellular influx in a mouse model of asthma. J Pharmacol Exp Ther. 2006; 320(3):1246-51. DOI: 10.1124/jpet.106.112250. View

10.

Klarenbeek J, Goedhart J, Hink M, Gadella T, Jalink K . A mTurquoise-based cAMP sensor for both FLIM and ratiometric read-out has improved dynamic range. PLoS One. 2011; 6(4):e19170. PMC: 3084777. DOI: 10.1371/journal.pone.0019170. View

11.

McBrayer D, Tal-Gan Y . Recent Advances in GLP-1 Receptor Agonists for Use in Diabetes Mellitus. Drug Dev Res. 2017; 78(6):292-299. PMC: 5602594. DOI: 10.1002/ddr.21404. View

12.

Thorens B . Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1. Proc Natl Acad Sci U S A. 1992; 89(18):8641-5. PMC: 49976. DOI: 10.1073/pnas.89.18.8641. View

13.

Leech C, Dzhura I, Chepurny O, Kang G, Schwede F, Genieser H . Molecular physiology of glucagon-like peptide-1 insulin secretagogue action in pancreatic β cells. Prog Biophys Mol Biol. 2011; 107(2):236-47. PMC: 3200499. DOI: 10.1016/j.pbiomolbio.2011.07.005. View

14.

Troke R, Tan T, Bloom S . The future role of gut hormones in the treatment of obesity. Ther Adv Chronic Dis. 2014; 5(1):4-14. PMC: 3871274. DOI: 10.1177/2040622313506730. View

15.

le Roux C, Aylwin S, Batterham R, Borg C, Coyle F, Prasad V . Gut hormone profiles following bariatric surgery favor an anorectic state, facilitate weight loss, and improve metabolic parameters. Ann Surg. 2005; 243(1):108-14. PMC: 1449984. DOI: 10.1097/01.sla.0000183349.16877.84. View

16.

Kieffer T, Habener J . The glucagon-like peptides. Endocr Rev. 1999; 20(6):876-913. DOI: 10.1210/edrv.20.6.0385. View

17.

Kim G, Lin J, Blomain E, Waldman S . Antiobesity pharmacotherapy: new drugs and emerging targets. Clin Pharmacol Ther. 2013; 95(1):53-66. PMC: 4054704. DOI: 10.1038/clpt.2013.204. View

18.

Steinert R, Poller B, Cristina Castelli M, Drewe J, Beglinger C . Oral administration of glucagon-like peptide 1 or peptide YY 3-36 affects food intake in healthy male subjects. Am J Clin Nutr. 2010; 92(4):810-7. DOI: 10.3945/ajcn.2010.29663. View

19.

Finan B, Yang B, Ottaway N, Smiley D, Ma T, Clemmensen C . A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat Med. 2014; 21(1):27-36. DOI: 10.1038/nm.3761. View

20.

Michel M, Beck-Sickinger A, Cox H, Doods H, Herzog H, Larhammar D . XVI. International Union of Pharmacology recommendations for the nomenclature of neuropeptide Y, peptide YY, and pancreatic polypeptide receptors. Pharmacol Rev. 1998; 50(1):143-50. View