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Multimeric Lactoside "Click Clusters" as Tools to Investigate the Effect of Linker Length in Specific Interactions with Peanut Lectin, Galectin-1, and-3

Gouin, Sebastien G.; Garcia Fernandez, Jose Manuel; Vanquelef, Enguerran; Dupradeau, Francois-Yves; Salomonsson, Emma LU ; Leffler, Hakon LU ; Ortega-Munoz, Mariano; Nilsson, Ulf LU and Kovensky, Jose (2010) In ChemBioChem 11(10). p.1430-1442
Abstract
Multimeric lactosides based on carbohydrate scaffolds with valencies ranging from 1 to 4 and different linker lengths were synthesized by a copper-catalyzed azide-alkyne cycloaddition (CuAAC). The binding affinities and crosslinking abilities of the new "click clusters" toward biologically relevant galectins (gal-1, gal-3) and peanut lectin were evaluated by fluorescent polarization assay (FPA) and enzyme-linked lectin assay (ELLA), respectively. FPA indicated that the binding affinities of the synthetic multilactosides towards the galectins increased proportionally with their lactosyl content, without significant differences due to the spacer length. ELLA evidenced a modest cluster effect for the multivalent conjugates, with a relative... (More)
Multimeric lactosides based on carbohydrate scaffolds with valencies ranging from 1 to 4 and different linker lengths were synthesized by a copper-catalyzed azide-alkyne cycloaddition (CuAAC). The binding affinities and crosslinking abilities of the new "click clusters" toward biologically relevant galectins (gal-1, gal-3) and peanut lectin were evaluated by fluorescent polarization assay (FPA) and enzyme-linked lectin assay (ELLA), respectively. FPA indicated that the binding affinities of the synthetic multilactosides towards the galectins increased proportionally with their lactosyl content, without significant differences due to the spacer length. ELLA evidenced a modest cluster effect for the multivalent conjugates, with a relative potency per lactoside ranging from 2.1 to 3.2. Nearly identical binding affinities were recorded for derivatives differing in the length of the linkers, in agreement with the FPA data. These results demonstrate that this parameter does not significantly influence the recognition process when interactions occur at a single lectin site. Molecular dynamics revealed that glycoconjugates adopt a pseudoglobular structure with a random localization of the lactoside residues. These spatial distributions were observed irrespective of the linker length; this explains the virtually equal affinities recorded by ELLA. In contrast, two-site "sandwich" ELLA clearly revealed that multivalent derivatives bearing the longest spacers were more efficient for crosslinking lectins. Intrinsic affinities, devoid of aggregation effects, and crosslinking capabilities are, therefore, not directly related phenomena that must be taking into consideration in neoglycoconjugate design for specific applications. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
molecular dynamics, linkers, lectins, carbohydrates, click chemistry
in
ChemBioChem
volume
11
issue
10
pages
1430 - 1442
publisher
John Wiley & Sons
external identifiers
  • wos:000280787400018
  • scopus:77954373398
ISSN
1439-4227
DOI
10.1002/cbic.201000167
language
English
LU publication?
yes
id
0833e1f7-b5f4-43ad-b3ef-427916898a7f (old id 1676868)
date added to LUP
2010-09-21 10:00:46
date last changed
2018-05-29 10:35:08
@article{0833e1f7-b5f4-43ad-b3ef-427916898a7f,
  abstract     = {Multimeric lactosides based on carbohydrate scaffolds with valencies ranging from 1 to 4 and different linker lengths were synthesized by a copper-catalyzed azide-alkyne cycloaddition (CuAAC). The binding affinities and crosslinking abilities of the new "click clusters" toward biologically relevant galectins (gal-1, gal-3) and peanut lectin were evaluated by fluorescent polarization assay (FPA) and enzyme-linked lectin assay (ELLA), respectively. FPA indicated that the binding affinities of the synthetic multilactosides towards the galectins increased proportionally with their lactosyl content, without significant differences due to the spacer length. ELLA evidenced a modest cluster effect for the multivalent conjugates, with a relative potency per lactoside ranging from 2.1 to 3.2. Nearly identical binding affinities were recorded for derivatives differing in the length of the linkers, in agreement with the FPA data. These results demonstrate that this parameter does not significantly influence the recognition process when interactions occur at a single lectin site. Molecular dynamics revealed that glycoconjugates adopt a pseudoglobular structure with a random localization of the lactoside residues. These spatial distributions were observed irrespective of the linker length; this explains the virtually equal affinities recorded by ELLA. In contrast, two-site "sandwich" ELLA clearly revealed that multivalent derivatives bearing the longest spacers were more efficient for crosslinking lectins. Intrinsic affinities, devoid of aggregation effects, and crosslinking capabilities are, therefore, not directly related phenomena that must be taking into consideration in neoglycoconjugate design for specific applications.},
  author       = {Gouin, Sebastien G. and Garcia Fernandez, Jose Manuel and Vanquelef, Enguerran and Dupradeau, Francois-Yves and Salomonsson, Emma and Leffler, Hakon and Ortega-Munoz, Mariano and Nilsson, Ulf and Kovensky, Jose},
  issn         = {1439-4227},
  keyword      = {molecular dynamics,linkers,lectins,carbohydrates,click chemistry},
  language     = {eng},
  number       = {10},
  pages        = {1430--1442},
  publisher    = {John Wiley & Sons},
  series       = {ChemBioChem},
  title        = {Multimeric Lactoside "Click Clusters" as Tools to Investigate the Effect of Linker Length in Specific Interactions with Peanut Lectin, Galectin-1, and-3},
  url          = {http://dx.doi.org/10.1002/cbic.201000167},
  volume       = {11},
  year         = {2010},
}