Half-Life Extending Modifications of Peptide YY Direct Receptor-Mediated Internalization.

Peptide YY (PYY) is an endogenous ligand of the neuropeptide Y receptor (YR), on which it acts to reduce food intake. Chemically modified PYY 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 PYY's pharmacokinetics but also affect central aspects of its pharmacodynamics. PEGylation of PYY inhibited endocytosis by increasing receptor dissociation rates (), which reduced arrestin-3 (Arr3) activity. This is the first link between Arr3 recruitment and YR residence time. C16-lipidation of PYY had a negligible impact on YR 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 G versus Arr3 signaling bias. We believe that this will be important for future design of peptide therapeutics.