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

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 F...

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Bibliographic Details
Published in:Scientific reports 2018-02, Vol.8 (1), p.3749-14, Article 3749
Main Authors: Chepurny, Oleg G., Bonaccorso, Ron L., Leech, Colin A., Wöllert, Torsten, Langford, George M., Schwede, Frank, Roth, Christian L., Doyle, Robert P., Holz, George G.
Format: Article
Language:English
Subjects:
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Adenosine
Adenosine receptors
Amino Acid Sequence
Amino acids
Appetite
Blood
Cyclic AMP
Diabetes mellitus
Diabetes mellitus (non-insulin dependent)
Fluorescence resonance energy transfer
Glucagon
Glucagon-like peptide 1
Glucagon-Like Peptide 1 - agonists
HEK293 Cells
Humanities and Social Sciences
Humans
Metabolic disorders
multidisciplinary
Peptides
Peptides - chemistry
Peptides - pharmacology
Receptors, Neuropeptide Y - agonists
Science
Science (multidisciplinary)
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Summary: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 2 receptor (NPY2R). EP45 fails to activate glucagon or GIP receptors, whereas for cells that co-express NPY2R and adenosine A 2B 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.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-018-22106-1