Chimeric peptide EP45 as a dual agonist at GLP-1 and NPY2R receptors.
Oleg G ChepurnyRon L BonaccorsoColin A LeechTorsten WöllertGeorge M LangfordFrank SchwedeChristian L RothRobert P DoyleGeorge G HolzPublished in: Scientific reports (2018)
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.
Keyphrases
- blood glucose
- living cells
- amino acid
- high throughput
- binding protein
- protein kinase
- weight loss
- fluorescent probe
- glycemic control
- single molecule
- cell therapy
- type diabetes
- signaling pathway
- blood pressure
- metabolic syndrome
- induced apoptosis
- insulin resistance
- stem cells
- healthcare
- cell cycle arrest
- body mass index
- oxidative stress
- cell death
- health information
- adipose tissue
- skeletal muscle
- quantum dots
- cell proliferation
- pi k akt
- high fat diet induced