Half-Life Extending Modifications of Peptide YY3–36 Direct Receptor-Mediated Internalization

• Published in: Molecular pharmaceutics 2019-08, Vol.16 (8), p.3665-3677
• Main Authors: Bech, Esben M, Kaiser, Anette, Bellmann-Sickert, Kathrin, Nielsen, Søren S.-R, Sørensen, Kasper K, Elster, Lisbeth, Hatzakis, Nikos, Pedersen, Søren L, Beck-Sickinger, Annette G, Jensen, Knud J
• Format: Article
• Language: English
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.9b00554

Peptide YY3–36 (PYY3–36) is an endogenous ligand of the neuropeptide Y2 receptor (Y2R), on which it acts to reduce food intake. Chemically modified PYY3–36 analogues with extended half-lives are potential therapeutics for the treatment of obesity. Here we show that the common half-life extending strategies PEGylation and lipidation not only control PYY3–36’s pharmacokinetics but also affect central aspects of its pharmacodynamics. PEGylation of PYY3–36 inhibited endocytosis by increasing receptor dissociation rates (k off), which reduced arrestin-3 (Arr3) activity. This is the first link between Arr3 recruitment and Y2R residence time. C16-lipidation of PYY3–36 had a negligible impact on Y2R signaling, binding, and endocytosis. In contrast, C18acid-lipidation minimized endocytosis, which indicated a decreased internalization through non-arrestin-related mechanisms. We propose a temporal model that connects the properties and position of the half-life extender with receptor Gi versus Arr3 signaling bias. We believe that this will be important for future design of peptide therapeutics.