Stereochemistry-Driven Interactions of α,γ-Peptide Ligands with the Neuropeptide Y Y4-Receptor

Eva Plut, Jacqueline C. Calderón, Vesna Stanojlovic, Albert Gattor, Carina Hörig, Laura Humphrys, Adam Konieczny, Sabine Kerres, Mario Schubert, Max Keller*, Chiara Cabrele*, Timothy Clark*, Oliver Reiser*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The G-protein-coupled Y4-receptor (Y4R) and its endogenous ligand, pancreatic polypeptide (PP), suppress appetite in response to food intake and, thus, are attractive drug targets for body-weight control. The C-terminus of human PP (hPP), T32-R33-P34-R35-Y36-NH2, penetrates deep into the binding pocket with its tyrosine-amide and di-arginine motif. Here, we present two C-terminally amidated α,γ-hexapeptides (1a/b) with sequence Ac-R31-γ-CBAA32-R33-L34-R35-Y36-NH2, where γ-CBAA is the (1R,2S,3R)-configured 2-(aminomethyl)-3-phenylcyclobutanecarboxyl moiety (1a) or its mirror image (1b). Both peptides bind the Y4R (Ki of 1a/b: 0.66/12 nM) and act as partial agonists (intrinsic activity of 1a/b: 50/39%). Their induced-fit binding poses in the Y4R pocket are unique and build ligand–receptor contacts distinct from those of the C-terminus of the endogenous ligand hPP. We conclude that energetically favorable interactions, although they do not match those of the native ligand hPP, still guarantee high binding affinity (with 1a rivaling hPP) but not the maximum receptor activation.
Original languageEnglish
Pages (from-to)9642-9657
JournalJournal of Medicinal Chemistry
Volume66
Issue number14
DOIs
Publication statusPublished - 13 Jul 2023

Bibliographical note

Publisher Copyright:
© 2023 The Authors. Published by American Chemical Society.

Keywords

  • Cyclobutanes
  • Humans
  • Ligands
  • Neuropeptide Y/metabolism
  • Pancreatic Polypeptide/metabolism
  • Receptors, Neuropeptide Y/metabolism

Fields of Science and Technology Classification 2012

  • 104 Chemistry

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