@misc{9222609,
  abstract     = {{Pancreatic polypeptide (PP) is a gut-derived hormone of the neuropeptide Y family that regulates appetite, gastrointestinal motility, and energy homeostasis through activation of the neuropeptide Y4 receptor (Y4R). With the rising prevalence of obesity, understanding the molecular pharmacology and structure-function relationships of PP-Y4R interactions is essential for the development of novel anti-obesity therapies.

In this thesis, Y4 receptor activation was investigated using pharmacokinetically enhanced PP analogues, C-terminally modified peptides, short oligopeptide mimetics, and a synthetic small-molecule ligand. Functional signaling was assessed in Cos7 cells expressing Y4R using BRET-based cAMP inhibition and IP3 accumulation assays.

The results demonstrate that removal of the DPP-4 cleavage site and lipidation at either the N-terminus or position 13 do not impair Y4R activation, supporting strategies to enhance PP stability without loss of function. C-terminal modifications of PP showed that the Tyr36 side chain is essential for Y4 receptor activation, whereas the C-terminal carboxamide is not, as loss of Tyr36 reduced potency or caused complete loss of function. Short oligopeptide mimetics activated Y4R mainly as low-potency partial agonists; peptides with tryptophan at position 34 showed the lowest potency, and one displayed partial antagonistic behavior, indicating that C-terminal substitutions can shift Y4R signaling away from agonism. The small-molecule compound (S)-VU0637120 markedly reduced PP potency and efficacy, suggesting it acts as a competitive antagonist.

Overall, this work provides structure-activity insights into Y4R activation and identifies key molecular determinants governing potency and efficacy, supporting the design of Y4R-targeted therapeutics for metabolic disorders.}},
  author       = {{Silva, Annika}},
  language     = {{eng}},
  note         = {{Student Paper}},
  title        = {{C-terminal Modifications and Short Oligopeptide Mimetics of Pancreatic Polypeptides in Y4 Receptor Activation}},
  year         = {{2026}},
}