Stereochemistry-Driven Interactions of α,γ-Peptide Ligands with the Neuropeptide Y Y 4 -Receptor

• Published in: Journal of medicinal chemistry Vol. 66; no. 14; pp. 9642 - 9657
• Main Authors: Plut, Eva, Calderón, Jacqueline C, Stanojlović, Vesna, Gattor, Albert O, Höring, Carina, Humphrys, Laura J, Konieczny, Adam, Kerres, Sabine, Schubert, Mario, Keller, Max, Cabrele, Chiara, Clark, Timothy, Reiser, Oliver
• Format: Journal Article
• Language: English
• Published: United States 27.07.2023
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c00363

The G-protein-coupled Y -receptor (Y R) 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), T -R -P -R -Y - , penetrates deep into the binding pocket with its tyrosine-amide and di-arginine motif. Here, we present two C-terminally amidated α,γ-hexapeptides ( / ) with sequence -R -γ-CBAA -R -L -R -Y - , where γ-CBAA is the (1 ,2 ,3 )-configured 2-(aminomethyl)-3-phenylcyclobutanecarboxyl moiety ( ) or its mirror image ( ). Both peptides bind the Y R ( of / : 0.66/12 nM) and act as partial agonists (intrinsic activity of / : 50/39%). Their induced-fit binding poses in the Y R 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 rivaling hPP) but not the maximum receptor activation.