Constrained glycopeptide ligands for MPRs. Limitations of unprotected phosphorylated building blocks

被引:34
作者
Franzyk, H
Christensen, MK
Jorgensen, RM
Meldal, M
Cordes, H
Mouritsen, S
Bock, K
机构
[1] CARLSBERG LAB, DEPT CHEM, DK-2500 VALBY, DENMARK
[2] DEPT BASIC IMMUNOL, DK-2100 COPENHAGEN, DENMARK
关键词
D O I
10.1016/S0968-0896(96)00194-0
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
A new methodology for the synthesis of cyclic and phosphorylated glycopeptide templates was developed. First, fully protected building blocks containing mannose and mannose disaccharides with bis-trichloroethyl phosphate on Fmoc-Thr-OPfp were synthesized. These were used in solid-phase assembly through side chain anchoring of glycosylated hexa- and octa-peptides protected at the C-terminal carboxylate as the allyl ester. Selective allyl ester cleavage and head-to-tail cyclization under pseudo-dilution conditions gave a high yield of pure cyclic peptide templates. Unprotected phosphate in the building block was evaluated as an alternative to the problematic trichloroethyl group. It was found that one unprotected phosphate is readily incorporated, whereas the second unprotected phosphorylated building block react very slowly due to electrostatic repulsion in the solid-phase synthesis. For comparison with previous binding studies modified glycopeptide templates containing only phosphorylated mannose monosaccharides or templates modified in the peptide part were synthesized. All the structures were tested for their binding to the mannose 6-phosphate receptor, and it was found that although mannose disaccharides are required for optimal interaction, the detailed structure of the peptide template has a strong influence on binding to the receptor. The restricted conformations of the cyclic peptides decreased the binding considerably. Copyright (C) 1997 Published by Elsevier Science Ltd.
引用
收藏
页码:21 / 40
页数:20
相关论文
共 38 条
[1]  
Auzanneau F I, 1995, J Pept Sci, V1, P31, DOI 10.1002/psc.310010106
[2]  
Barany G., 1979, PEPTIDES A, V2, P1
[3]   SYNTHESIS OF GLYCOSYLATED PEPTIDE TEMPLATES CONTAINING 6'-O-PHOSPHORYLATED MANNOSE DISACCHARIDES AND THEIR BINDING TO THE CATION-INDEPENDENT MANNOSE 6-PHOSPHATE RECEPTOR [J].
CHRISTENSEN, MK ;
MELDAL, M ;
BOCK, K ;
CORDES, H ;
MOURITSEN, S ;
ELSNER, H .
JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1, 1994, (10) :1299-1310
[4]   SYNTHESIS OF MANNOSE 6-PHOSPHATE-CONTAINING DISACCHARIDE THREONINE BUILDING-BLOCKS AND THEIR USE IN SOLID-PHASE GLYCOPEPTIDE SYNTHESIS [J].
CHRISTENSEN, MK ;
MELDAL, M ;
BOCK, K .
JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1, 1993, (13) :1453-1460
[5]   PROTECTED-MODE SYNTHESIS OF N-LINKED GLYCOPEPTIDES - SINGLE-STEP PREPARATION OF BUILDING-BLOCKS AS PERACETYL GLYCOSYLATED N-ALPHA-FMOC ASPARAGINE OPFP ESTERS [J].
CHRISTIANSENBRAMS, I ;
MELDAL, M ;
BOCK, K .
JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1, 1993, (13) :1461-1471
[6]  
DISTLER JJ, 1991, J BIOL CHEM, V266, P21687
[7]   CYCLIC HEXAPEPTIDES AND CHIMERIC PEPTIDES AS MIMICS OF TENDAMISTAT [J].
ETZKORN, FA ;
GUO, T ;
LIPTON, MA ;
GOLDBERG, SD ;
BARTLETT, PA .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1994, 116 (23) :10412-10425
[8]   SYNTHESIS OF ALIPHATIC O-DIMANNOSYL AMINO-ACID BUILDING-BLOCKS FOR SOLID-PHASE ASSEMBLY OF GLYCOPEPTIDE LIBRARIES [J].
FRANZYK, H ;
MELDAL, M ;
PAULSEN, H ;
BOCK, K .
JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1, 1995, (22) :2883-2898
[9]   POTENTIAL PYROPHOSPHATE FORMATION UPON USE OF N-ALPHA-FMOC-TYR(PO3H2)-OH IN SOLID-PHASE PEPTIDE-SYNTHESIS [J].
GARCIAECHEVERRIA, C .
LETTERS IN PEPTIDE SCIENCE, 1995, 2 (02) :93-98
[10]   THE PARA-NITROPHENYLETHYL (NPE) GROUP - A VERSATILE NEW BLOCKING GROUP FOR PHOSPHATE AND AGLYCONE PROTECTION IN NUCLEOSIDES AND NUCLEOTIDES [J].
HIMMELSBACH, F ;
SCHULZ, BS ;
TRICHTINGER, T ;
CHARUBALA, R ;
PFLEIDERER, W .
TETRAHEDRON, 1984, 40 (01) :59-72