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Angew Chem Int Ed Engl. 2014 Sep 15;53(38):10067-71. doi: 10.1002/anie.201403750. Epub 2014 Jul 25.

Peptide modifications differentially alter G protein-coupled receptor internalization and signaling bias.

Author information

1
Universität Leipzig, Faculty of Biosciences, Pharmacy and Psychology, Institute of Biochemistry, Brüderstrasse 34, 04103 Leipzig (Germany) http://www.biochemie.uni-leipzig.de/agbs/

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.

KEYWORDS:

PEGylation; biased ligands; lipidation; peptides; receptors

PMID:
25065900
PMCID:
PMC4704863
DOI:
10.1002/anie.201403750
[Indexed for MEDLINE]
Free PMC Article

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