Thiodigalactoside-Bovine Serum Albumin Conjugates as High-Potency Inhibitors of Galectin-3: An Outstanding Example of Multivalent Presentation of Small Molecule Inhibitors

Bioconjugate Chemistry
Hao ZhangRoland J Pieters

Abstract

Galectin inhibitors are urgently needed to understand the mode of action and druggability of different galectins, but potent and selective agents still evade researchers. Small-sized inhibitors based on thiodigalactoside (TDG) have shown their potential while modifications at their C3 position indicated a strategy to improve selectivity and potency. Considering the role of galectins as glycoprotein traffic police, involved in multivalent bridging interactions, we aimed to create multivalent versions of the potent TDG inhibitors. We herein present for the first time the multivalent attachment of a TDG derivative using bovine serum albumin (BSA) as the scaffold. An efficient synthetic method is presented to obtain a novel type of neoglycosylated proteins loaded with different numbers of TDG moieties. A polyethylene glycol (PEG)-spacer is introduced between the TDG and the protein scaffold maintaining appropriate accessibility for an adequate galectin interaction. The novel conjugates were evaluated in galectin binding and inhibition studies in vitro. The conjugate with a moderate density of 19 conjugated TDGs was identified as one of the most potent multivalent Gal-3 inhibitors so far, with a clear demonstration of the benefit of...Continue Reading

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Citations

Sep 22, 2018·Journal of Nanobiotechnology·P BojarováV Křen
Dec 6, 2019·Organic & Biomolecular Chemistry·Diksha HaksarRoland J Pieters
Mar 10, 2020·Journal of Immunology Research·Ziyu GaoLiming Yang
Feb 2, 2021·ACS Biomaterials Science & Engineering·Jie WangJian Dong
Jan 2, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Karima BelkhademRené Roy
May 20, 2021·Macromolecular Bioscience·Marina Rodrigues TavaresTomáš Etrych
Jul 3, 2021·International Journal of Molecular Sciences·Sara BertuzziJesús Jiménez-Barbero
Aug 5, 2021·Chemical Society Reviews·Yujun KimInjae Shin

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Methods Mentioned

BETA
column chromatography
electrophoresis
ELISA
fluorescence polarization
size-exclusion chromatography

Software Mentioned

SigmaPlot

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