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

Caroline T. Kriss, Bih Show Lou, Lajos Z. Szabò, Scott A. Mitchell, Victor J. Hruby, Robin Polt

Research output: Contribution to journalArticle

21 Scopus citations

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-NH2, 2, and H-Tyr-c-[D-Cys-Gly-Phe-D-Cys]-Ser(α-O-Glcp)-Gly-NH2, 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-NH2, 1, to determine the impact of glycosylation on peptide conformation. The only observed conformational effects were on the residue of attachment, Ser6, and on the adjacent Gly7-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. Copyright (C) 2000 Elsevier Science Ltd.

Original languageEnglish (US)
Pages (from-to)9-25
Number of pages17
JournalTetrahedron Asymmetry
Volume11
Issue number1
DOIs
StatePublished - Jan 28 2000

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ASJC Scopus subject areas

  • Catalysis
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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