Role of the sugar moiety on the opioid receptor binding and conformation of a series of enkephalin neoglycopeptides

Mònica Rosa, Verónica Gonzalez-Nunez, Katherine Barreto-Valer, Filipa Marcelo, Julia Sánchez-Sánchez, Luis P. Calle, Juan C. Arévalo, Raquel E. Rodríguez, Jesús Jiménez-Barbero, Gemma Arsequell, Gregorio Valencia

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2260-2265
Number of pages6
JournalBioorganic and Medicinal Chemistry
Volume25
Issue number7
DOIs
Publication statusPublished - 1 Jan 2017

Keywords

  • Enkephalin-related
  • Glycosylation
  • Neoglycopeptides
  • Neuropeptide
  • Opioid receptors
  • Pharmacology

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