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Multivalent Fucosides Targeting β-Propeller Lectins from Lung Pathogens with Promising Anti-Adhesive Properties
[Image: see text] Fungal and bacterial pathogens causing lung infections often use lectins to mediate adhesion to glycoconjugates at the surface of host tissues. Given the rapid emergence of resistance to the treatments in current use, β-propeller lectins such as FleA from Aspergillus fumigatus, Sap...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9764287/ https://www.ncbi.nlm.nih.gov/pubmed/36414265 http://dx.doi.org/10.1021/acschembio.2c00708 |
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author | Duca, Margherita Haksar, Diksha van Neer, Jacq Thies-Weesie, Dominique M.E. Martínez-Alarcón, Dania de Cock, Hans Varrot, Annabelle Pieters, Roland J. |
author_facet | Duca, Margherita Haksar, Diksha van Neer, Jacq Thies-Weesie, Dominique M.E. Martínez-Alarcón, Dania de Cock, Hans Varrot, Annabelle Pieters, Roland J. |
author_sort | Duca, Margherita |
collection | PubMed |
description | [Image: see text] Fungal and bacterial pathogens causing lung infections often use lectins to mediate adhesion to glycoconjugates at the surface of host tissues. Given the rapid emergence of resistance to the treatments in current use, β-propeller lectins such as FleA from Aspergillus fumigatus, SapL1 from Scedosporium apiospermum, and BambL from Burkholderia ambifaria have become appealing targets for the design of anti-adhesive agents. In search of novel and cheap anti-infectious agents, we synthesized multivalent compounds that can display up to 20 units of fucose, the natural ligand. We obtained nanomolar inhibitors that are several orders of magnitude stronger than their monovalent analogue according to several biophysical techniques (i.e., fluorescence polarization, isothermal titration calorimetry, and bio-layer interferometry). The reason for high affinity might be attributed to a strong aggregating mechanism, which was examined by analytical ultracentrifugation. Notably, the fucosylated inhibitors reduced the adhesion of A. fumigatus spores to lung epithelial cells when administered 1 h before or after the infection of human lung epithelial cells. For this reason, we propose them as promising anti-adhesive drugs for the prevention and treatment of aspergillosis and related microbial lung infections. |
format | Online Article Text |
id | pubmed-9764287 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-97642872022-12-21 Multivalent Fucosides Targeting β-Propeller Lectins from Lung Pathogens with Promising Anti-Adhesive Properties Duca, Margherita Haksar, Diksha van Neer, Jacq Thies-Weesie, Dominique M.E. Martínez-Alarcón, Dania de Cock, Hans Varrot, Annabelle Pieters, Roland J. ACS Chem Biol [Image: see text] Fungal and bacterial pathogens causing lung infections often use lectins to mediate adhesion to glycoconjugates at the surface of host tissues. Given the rapid emergence of resistance to the treatments in current use, β-propeller lectins such as FleA from Aspergillus fumigatus, SapL1 from Scedosporium apiospermum, and BambL from Burkholderia ambifaria have become appealing targets for the design of anti-adhesive agents. In search of novel and cheap anti-infectious agents, we synthesized multivalent compounds that can display up to 20 units of fucose, the natural ligand. We obtained nanomolar inhibitors that are several orders of magnitude stronger than their monovalent analogue according to several biophysical techniques (i.e., fluorescence polarization, isothermal titration calorimetry, and bio-layer interferometry). The reason for high affinity might be attributed to a strong aggregating mechanism, which was examined by analytical ultracentrifugation. Notably, the fucosylated inhibitors reduced the adhesion of A. fumigatus spores to lung epithelial cells when administered 1 h before or after the infection of human lung epithelial cells. For this reason, we propose them as promising anti-adhesive drugs for the prevention and treatment of aspergillosis and related microbial lung infections. American Chemical Society 2022-11-22 2022-12-16 /pmc/articles/PMC9764287/ /pubmed/36414265 http://dx.doi.org/10.1021/acschembio.2c00708 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Duca, Margherita Haksar, Diksha van Neer, Jacq Thies-Weesie, Dominique M.E. Martínez-Alarcón, Dania de Cock, Hans Varrot, Annabelle Pieters, Roland J. Multivalent Fucosides Targeting β-Propeller Lectins from Lung Pathogens with Promising Anti-Adhesive Properties |
title | Multivalent Fucosides
Targeting β-Propeller
Lectins from Lung Pathogens with Promising Anti-Adhesive Properties |
title_full | Multivalent Fucosides
Targeting β-Propeller
Lectins from Lung Pathogens with Promising Anti-Adhesive Properties |
title_fullStr | Multivalent Fucosides
Targeting β-Propeller
Lectins from Lung Pathogens with Promising Anti-Adhesive Properties |
title_full_unstemmed | Multivalent Fucosides
Targeting β-Propeller
Lectins from Lung Pathogens with Promising Anti-Adhesive Properties |
title_short | Multivalent Fucosides
Targeting β-Propeller
Lectins from Lung Pathogens with Promising Anti-Adhesive Properties |
title_sort | multivalent fucosides
targeting β-propeller
lectins from lung pathogens with promising anti-adhesive properties |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9764287/ https://www.ncbi.nlm.nih.gov/pubmed/36414265 http://dx.doi.org/10.1021/acschembio.2c00708 |
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