PUBLICATION

Synthesis, biological evaluation and structural characterization of novel glycopeptide analogues of nociceptin N/OFQ

Authors
Arsequell, G., Rosa, M., Mayato, C., Dorta, R.L., Gonzalez-Nunez, V., Barreto-Valer, K., Marcelo, F., Calle, L.P., Vázquez, J.T., Rodríguez, R.E., Jiménez-Barbero, J., and Valencia, G.
ID
ZDB-PUB-110721-11
Date
2011
Source
Organic & biomolecular chemistry   9(17): 6133-42 (Journal)
Registered Authors
González Nuñez, Veronica
Keywords
none
MeSH Terms
  • Amino Acid Sequence
  • Animals
  • Binding, Competitive
  • Cell Line
  • Glycopeptides/chemical synthesis
  • Glycopeptides/chemistry*
  • Glycopeptides/pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Opioid Peptides/chemical synthesis
  • Opioid Peptides/chemistry*
  • Opioid Peptides/pharmacology*
  • Protein Binding
  • Receptors, G-Protein-Coupled/metabolism*
  • Receptors, Opioid/agonists
  • Zebrafish
PubMed
21773621 Full text @ Org. Biomol. Chem.
Citation
Arsequell, G., Rosa, M., Mayato, C., Dorta, R.L., Gonzalez-Nunez, V., Barreto-Valer, K., Marcelo, F., Calle, L.P., Vázquez, J.T., Rodríguez, R.E., Jiménez-Barbero, J., and Valencia, G. (2011) Synthesis, biological evaluation and structural characterization of novel glycopeptide analogues of nociceptin N/OFQ. Organic & biomolecular chemistry. 9(17):6133-42.
Abstract

To examine if the biological activity of the N/OFQ peptide, which is the native ligand of the pain-related and viable drug target NOP receptor, could be modulated by glycosylation and if such effects could be conformationally related, we have synthesized three N/OFQ glycopeptide analogues, namely: [Thr5-O-α-D-GalNAc-N/OFQ] (glycopeptide 1), [Ser10-O-α-D-GalNAc]-N/OFQ (glycopeptide 2) and [Ser10-O-β-D-GlcNAc]-N/OFQ] (glycopeptide 3). They were tested for biological activity in competition binding assays using the zebrafish animal model in which glycopeptide 2 exhibited a slightly improved binding affinity, whereas glycopeptide 1 showed a remarkably reduced binding affinity compared to the parent compound and glycopeptide 3. The structural analysis of these glycopeptides and the parent N/OFQ peptide by NMR and circular dichroism indicated that their aqueous solutions are mainly populated by random coil conformers. However, in membrane mimic environments a certain proportion of the molecules of all these peptides exist as α-helix structures. Interestingly, under these experimental conditions, glycopeptide 1 (glycosylated at Thr-5) exhibited a population of folded hairpin-like geometries. From these facts it is tempting to speculate that nociceptin analogues showing linear helical structures are more complementary and thus interact more efficiently with the native NOP receptor than folded structures, since glycopeptide 1 showed a significantly reduced binding affinity for the NOP receptor.

Genes / Markers
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
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