ZFIN ID: ZDB-PUB-170313-3
Role of the sugar moiety on the opioid receptor binding and conformation of a series of enkephalin neoglycopeptides
Rosa, M., Gonzalez-Nunez, V., Barreto-Valer, K., Marcelo, F., Sánchez-Sánchez, J., Calle, L.P., Arévalo, J.C., Rodríguez, R.E., Jiménez-Barbero, J., Arsequell, G., Valencia, G.
Date: 2017
Source: Bioorganic & Medicinal Chemistry   25(7): 2260-2265 (Journal)
Registered Authors: González Nuñez, Veronica
Keywords: Enkephalin-related, Glycosylation, Neoglycopeptides, Neuropeptide, Opioid receptors, Pharmacology
MeSH Terms:
  • Animals
  • Carbohydrates/chemistry*
  • Enkephalins/chemistry*
  • Glycopeptides/chemistry
  • Glycopeptides/metabolism*
  • Glycosylation
  • Magnetic Resonance Spectroscopy
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Protein Conformation
  • Receptors, Opioid/metabolism*
  • Structure-Activity Relationship
PubMed: 28284867 Full text @ Bioorg. Med. Chem.
Glycosylation by simple sugars is a drug discovery alternative that has been explored with varying success for enhancing the potency and bioavailability of opioid peptides. Long ago we described two O-glycosides having either β-Glucose and β-Galactose of (d-Met2, Pro5)-enkephalinamide showing one of the highest antinociceptive activities known. Here, we report the resynthesis of these two analogs and the preparation of three novel neoglycopeptide derivatives (α-Mannose, β-Lactose and β-Cellobiose). Binding studies to cloned zebrafish opioid receptors showed very small differences of affinity between the parent compound and the five glycopeptides thus suggesting that the nature of the carbohydrate moiety plays a minor role in determining the binding mode. Indeed, NMR conformational studies, combined with molecular mechanics calculations, indicated that all glycopeptides present the same major conformation either in solution or membrane-like environment. The evidences provided here highlight the relevance for in vivo activity of the conjugating bond between the peptide and sugar moieties in opioid glycopeptides.