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Thiodigalactoside–Bovine Serum Albumin Conjugates as High-Potency Inhibitors of Galectin-3: An Outstanding Example of Multivalent Presentation of Small Molecule Inhibitors
[Image: see text] 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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2018
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5909177/ https://www.ncbi.nlm.nih.gov/pubmed/29474087 http://dx.doi.org/10.1021/acs.bioconjchem.8b00047 |
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author | Zhang, Hao Laaf, Dominic Elling, Lothar Pieters, Roland J. |
author_facet | Zhang, Hao Laaf, Dominic Elling, Lothar Pieters, Roland J. |
author_sort | Zhang, Hao |
collection | PubMed |
description | [Image: see text] 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 a multivalent ligand presentation. The described method may facilitate the development of specific galectin inhibitors and their application in biomedical research. |
format | Online Article Text |
id | pubmed-5909177 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-59091772018-04-23 Thiodigalactoside–Bovine Serum Albumin Conjugates as High-Potency Inhibitors of Galectin-3: An Outstanding Example of Multivalent Presentation of Small Molecule Inhibitors Zhang, Hao Laaf, Dominic Elling, Lothar Pieters, Roland J. Bioconjug Chem [Image: see text] 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 a multivalent ligand presentation. The described method may facilitate the development of specific galectin inhibitors and their application in biomedical research. American Chemical Society 2018-02-23 2018-04-18 /pmc/articles/PMC5909177/ /pubmed/29474087 http://dx.doi.org/10.1021/acs.bioconjchem.8b00047 Text en Copyright © 2018 American Chemical Society This is an open access article published under a Creative Commons Non-Commercial No Derivative Works (CC-BY-NC-ND) Attribution License (http://pubs.acs.org/page/policy/authorchoice_ccbyncnd_termsofuse.html) , which permits copying and redistribution of the article, and creation of adaptations, all for non-commercial purposes. |
spellingShingle | Zhang, Hao Laaf, Dominic Elling, Lothar Pieters, Roland J. Thiodigalactoside–Bovine Serum Albumin Conjugates as High-Potency Inhibitors of Galectin-3: An Outstanding Example of Multivalent Presentation of Small Molecule Inhibitors |
title | Thiodigalactoside–Bovine Serum Albumin Conjugates
as High-Potency Inhibitors of Galectin-3: An Outstanding Example of
Multivalent Presentation of Small Molecule Inhibitors |
title_full | Thiodigalactoside–Bovine Serum Albumin Conjugates
as High-Potency Inhibitors of Galectin-3: An Outstanding Example of
Multivalent Presentation of Small Molecule Inhibitors |
title_fullStr | Thiodigalactoside–Bovine Serum Albumin Conjugates
as High-Potency Inhibitors of Galectin-3: An Outstanding Example of
Multivalent Presentation of Small Molecule Inhibitors |
title_full_unstemmed | Thiodigalactoside–Bovine Serum Albumin Conjugates
as High-Potency Inhibitors of Galectin-3: An Outstanding Example of
Multivalent Presentation of Small Molecule Inhibitors |
title_short | Thiodigalactoside–Bovine Serum Albumin Conjugates
as High-Potency Inhibitors of Galectin-3: An Outstanding Example of
Multivalent Presentation of Small Molecule Inhibitors |
title_sort | thiodigalactoside–bovine serum albumin conjugates
as high-potency inhibitors of galectin-3: an outstanding example of
multivalent presentation of small molecule inhibitors |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5909177/ https://www.ncbi.nlm.nih.gov/pubmed/29474087 http://dx.doi.org/10.1021/acs.bioconjchem.8b00047 |
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