Development and characterisation of a peptidergic N-and C-terminally stabilised mammalian NPY1R agonist which protects against diabetes induction

• Published in: Biochimica et biophysica acta. General subjects Vol. 1864; no. 5; p. 129543
• Main Authors: Lafferty, Ryan A., Tanday, Neil, Flatt, Peter R., Irwin, Nigel
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2020
• Subjects: agonists; animal disease models; apoptosis; Beta-cell; bioassays; body weight; Diabetes; dipeptides; Enzymatic stability; enzyme stability; enzymes; fish; glucagon; glucose; glucose tolerance; insulin; islets of Langerhans; mice; Peptide YY (PYY); Petromyzon marinus; phylogeny; Sea lamprey; therapeutics; Enzymatic stability; Beta-cell; Sea lamprey; Diabetes; Peptide YY (PYY)
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2020.129543

PYY (1–36) peptides from phylogenetically ancient fish, such as sea lamprey, have previously been shown to function as specific neuropeptide Y1 receptor (NPYR1) agonists. Although, sea lamprey PYY (1–36) is N-terminally stable, we reveal in this study that the peptide is subject to endopeptidase mediated C-terminal dipeptide degradation. In an attempt to prevent this, (d-Arg35)-sea lamprey PYY (1–36) was developed. In vitro bioassays assessed enzymatic stability, insulinostatic activity as well as beta-cell anti-apoptotic actions of (d-Arg35)-sea lamprey PYY (1–36). Follow-up studies examined the impact of twice daily administration of sea lamprey PYY (1–36) or (d-Arg35)-sea lamprey PYY (1–36) in multiple low dose STZ-induced diabetic mice. (d-Arg35)-sea lamprey PYY (1–36) was fully resistant to plasma enzymatic degradation. The peptide possessed similar significant insulinostatic, as well as positive anti-apoptotic biological actions, as the parent peptide. Sea lamprey PYY (1–36) and (d-Arg35)-sea lamprey PYY (1–36) delayed diabetes progression in STZ mice. Both treatment interventions induced a significant decrease in body weight, food and fluid intake as well as glucose and glucagon concentrations. In addition, glucose tolerance, plasma and pancreatic insulin were partially normalised. (d-Arg35)-sea lamprey PYY (1–36) was significantly more effective than sea lamprey PYY (1–36) in terms of enhancing glucose-stimulate insulin release. Both treatments improved pancreatic islet morphology, linked to decreased apoptosis of beta-cells. We present (d-Arg35)-sea lamprey PYY (1–36) as the first-in-class N- and C-terminally stable PYY (1–36) peptide analogue. Enzymatically stable, long-acting PYY (1–36) peptides highlight the therapeutic benefits of sustained activation of NPYR1's in diabetes. •Sea lamprey PYY (1–36) is N-terminally stable but subject to C-terminal degradation.•(d-Arg35)-sea lamprey PYY (1–36) is an N- and C-terminally stabilised PYY (1–36) peptide.•(d-Arg35)-sea lamprey PYY (1–36) retained bioactivity at the NPYR1 receptor.•(d-Arg35)-sea lamprey PYY (1–36) helps to protect against diabetes induction in mice.•Fully enzymatically stable PYY (1–36) peptides may have therapeutic benefits for diabetes.