Branching mode in complex-type triantennary N-glycans as regulatory element of their ligand properties

被引:41
作者
André, Sabine
Kojima, Shuji
Gundel, Gislinde
Russwurm, Roland
Schratt, Xaver
Unverzagt, Carlo
Gabius, Hans-Joachim
机构
[1] Univ Munich, Fac Med Vet, Inst Physiol Chem, D-80539 Munich, Germany
[2] Tokyo Univ Sci, Fac Pharmaceut Sci, Noda, Chiba 2788510, Japan
[3] Univ Bayreuth, D-95440 Bayreuth, Germany
来源
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS | 2006年 / 1760卷 / 05期
关键词
agglutinin; drug targeting; lectin; sialylation; tumor imaging;
D O I
10.1016/j.bbagen.2005.12.021
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
We address the question whether the two natural types of branching in complex-type triantennary N-glycans differ in ligand properties. Toward this end, we prepared the set of pergalactosylated undecasaccharides and derivatives with alpha 2,3/6-sialylation by chemoenzymatic synthesis. Conjugation resulted in neoglycoproteins which were tested in assays with lectins/antibodies, cultured cells and animals. Solid-phase assays with galactoside-specific proteins (a plant toxin, galectins and an antibody fraction) disclosed that the branching mode did not significantly affect affinity. However, compared to previous studies under identical conditions increase in antennae number and presence of substitutions in biantennary N-glycans altered K(D)-values with differences between receptors. Neoglycoprotein binding to cells of eight human tumor lines was sensitive to N-glycan branching. Staining intensity revealed pronounced branch-mode-dependent differences in four cases. Biodistribution profiles in mice uncovered dramatic changes in clearance rates with prolonged serum presence associated with type II branching of sialylated N-glycans and markedly increased uptake of neoglycoproteins with type I-branched N-glycans into liver, spleen, heart and lungs. This part of the study is relevant for rational glycoengineering of pharmaproteins. In general, our study supports the concept to view details of N-glycan structure, here branching, as a means to modulate ligand properties. (c) 2005 Elsevier B.V. All rights reserved.
引用
收藏
页码:768 / 782
页数:15
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