Enkephalin-based drug design: conformational analysis of O-linked glycopeptides by NMR and molecular modeling

Abstract

Glycosylation provides an effective means of enhancing penetration of the blood–brain barrier by pharmacologically active peptides. Glycosylated enkephalin analogues demonstrate much greater analgesic effects than their unglycosylated counterparts when administered peripherally. The solution conformations of glycopeptide enkephalin analogues with the sequences H-Tyr-c-[ d-Cys-Gly-Phe- d-Cys]-Ser(β- O-Glcp)-Gly-NH 2, 2, and H-Tyr-c-[ d-Cys-Gly-Phe- d-Cys]-Ser(α- O-Glcp)-Gly-NH 2, 3, have been determined by NMR and molecular modeling, and were compared to the unglycosylated peptide H-Tyr-c-[ d-Cys-Gly-Phe- d-Cys]-Ser-Gly-NH 2, 1, to determine the impact of glycosylation on peptide conformation. The only observed conformational effects were on the residue of attachment, Ser 6, and on the adjacent Gly 7-amide. This has important implications in peptide-based drug design in that strategically placed glycosylation can improve transport without destruction of the receptor selectivity of a pre-existing non-glycosylated peptide pharmacophore.