Glycopeptide-membrane interactions: Glycosyl enkephalin analogues adopt turn conformations by NMR and CD in amphipathic media

Michael M. Palian, V. I. Boguslavsky, David F. O'Brien, Robin L Polt

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

Four enkephalin analogues (Tyr-D-Thr-Gly-Phe-Leu-Ser-CONH2, 1, and the related O-linked glycopeptides bearing the monosaccharide β-glucose, 2, the disaccharide β-maltose, 3, and the trisaccharide β-maltotriose, 4) were synthesized, purified by HPLC, and biophysical studies were conducted to examine their interactions with membrane model systems. Glycopeptide 2 has been previously reported to penetrate the blood-brain barrier (BBB), and produce potent analgesia superior to morphine in mice (J. Med. Chem. 2000, 43, 2586-90 and J. Pharm. Exp. Ther. 2001, 299, 967-972). The parent peptide and its three glycopeptide derivatives were studied in aqueous solution and in the presence of micelles using 2-D NMR, CD, and molecular mechanics (Monte Carlo studies). Consistent with previous conformational studies on cyclic opioid agonist glycopeptides, it was seen that glycosylation did not significantly perturb the peptide backbone in aqueous solution, but all four compounds strongly associated with 5-30 mM SDS or DPC micelles, and underwent profound membrane-induced conformational changes. Interaction was also observed with POPC:POPE:cholesterol lipid vesicles (LUV) in equilibrium dialysis experiments. Although the peptide backbones of 1-4 possessed random coil structures in water, in the presence of the lipid phase they each formed a nearly identical pair of structures, all with a stable β-turn motif at the C-terminus. Use of spin labels (Mn2+ and 5-DOXYL-stearic acid) allowed for the determination of the position and orientation of the compounds relative to the surface of the micelle.

Original languageEnglish (US)
Pages (from-to)5823-5831
Number of pages9
JournalJournal of the American Chemical Society
Volume125
Issue number19
DOIs
StatePublished - May 14 2003

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Glycopeptides
Enkephalins
Conformations
Micelles
Nuclear magnetic resonance
Peptides
Membranes
Lipids
Bearings (structural)
Glycosylation
Maltose
Spin Labels
Trisaccharides
Molecular mechanics
Stearic acid
Dialysis
Monosaccharides
Disaccharides
Cholesterol
Mechanics

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Glycopeptide-membrane interactions : Glycosyl enkephalin analogues adopt turn conformations by NMR and CD in amphipathic media. / Palian, Michael M.; Boguslavsky, V. I.; O'Brien, David F.; Polt, Robin L.

In: Journal of the American Chemical Society, Vol. 125, No. 19, 14.05.2003, p. 5823-5831.

Research output: Contribution to journalArticle

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