TY - JOUR
T1 - Enkephalin-based drug design
T2 - Conformational analysis of O-linked glycopeptides by NMR and molecular modeling
AU - Kriss, Caroline T.
AU - Lou, Bih Show
AU - Szabò, Lajos Z.
AU - Mitchell, Scott A.
AU - Hruby, Victor J.
AU - Polt, Robin
N1 - Funding Information:
We would like to thank the U.S. Public Health Service National Institute for Drug Abuse (grant DA06284) and the National Science Foundation (grant CHE-9526909) for their support. We would also like to thank Protein Technologies of Tucson, AZ, for the loan of a prototype automated solid-phase peptide synthesizer.
PY - 2000/1/28
Y1 - 2000/1/28
N2 - 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.
AB - 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.
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U2 - 10.1016/S0957-4166(99)00544-3
DO - 10.1016/S0957-4166(99)00544-3
M3 - Article
AN - SCOPUS:0034001614
SN - 0957-4166
VL - 11
SP - 9
EP - 25
JO - Tetrahedron Asymmetry
JF - Tetrahedron Asymmetry
IS - 1
ER -