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Peptide Modifications Differentially Alter G Protein‐Coupled Receptor Internalization and Signaling Bias
Author(s) -
Mäde Veronika,
Babilon Stefanie,
Jolly Navjeet,
Wanka Lizzy,
BellmannSickert Kathrin,
Diaz Gimenez Luis E.,
Mörl Karin,
Cox Helen M.,
Gurevich Vsevolod V.,
BeckSickinger Annette G.
Publication year - 2014
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201403750
Subject(s) - internalization , receptor , microbiology and biotechnology , signal transduction , chemistry , biophysics , biology , biochemistry
Although G protein‐coupled receptors (GPCRs) are targeted by more clinically used drugs than any other type of protein, their ligand development is particularly challenging. Humans have four neuropeptide Y receptors: hY 1 R and hY 5 R are orexigenic, while hY 2 R and hY 4 R are anorexigenic, and represent important anti‐obesity drug targets. We show for the first time that PEGylation and lipidation, chemical modifications that prolong the plasma half‐lives of peptides, confer additional benefits. Both modifications enhance pancreatic polypeptide preference for hY 2 R/hY 4 R over hY 1 R/hY 5 R. Lipidation biases the ligand towards arrestin recruitment and internalization, whereas PEGylation confers the opposite bias. These effects were independent of the cell system and modified residue. We thus provide novel insights into the mode of action of peptide modifications and open innovative venues for generating peptide agonists with extended therapeutic potential.