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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...

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Autores principales: Duca, Margherita, Haksar, Diksha, van Neer, Jacq, Thies-Weesie, Dominique M.E., Martínez-Alarcón, Dania, de Cock, Hans, Varrot, Annabelle, Pieters, Roland J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
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.
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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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