title: Peptide modifications differentially alter G protein-coupled receptor internalization and signaling bias.
abstract: 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: hY1R and hY5R are orexigenic, while hY2R and hY4R 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 hY2R/hY4R over hY1R/hY5R. 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.
authors: Universität Leipzig, Faculty of Biosciences, Pharmacy and Psychology, Institute of Biochemistry, Brüderstrasse 34, 04103 Leipzig (Germany) http://www.biochemie.uni-leipzig.de/agbs/
authors: Veronika
authors: V
authors: Mäde
authors: Stefanie
authors: S
authors: Babilon
authors: Navjeet
authors: N
authors: Jolly
authors: Lizzy
authors: L
authors: Wanka
authors: Kathrin
authors: K
authors: Bellmann-Sickert
authors: Luis E
authors: LE
authors: Diaz Gimenez
authors: Karin
authors: K
authors: Mörl
authors: Helen M
authors: HM
authors: Cox
authors: Vsevolod V
authors: VV
authors: Gurevich
authors: Annette G
authors: AG
authors: Beck-Sickinger
mesh_terms: D057809:HEK293 Cells; D006801:Humans; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D010455:Peptides; D043562:Receptors, G-Protein-Coupled
keywords: PEGylation; biased ligands; lipidation; peptides; receptors