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Hexavalent thiofucosides to probe the role of the Aspergillus fumigatus lectin FleA in fungal pathogenicity

Abstract : A. fumigatus is a pathogenic fungus infecting the respiratory system and responsible for a variety of life-threatening lung diseases. A fucose-binding lectin named FleA which has a controversial role in A. fumigatus pathogenesis was recently identified. New chemical probes with high affinity and enzymatic stability are needed to explore the role of FleA in the infection process. In this study, we developed potent FleA antagonists based on optimized and non-hydrolysable thiofucoside ligands. We first synthesized a set of monovalent sugars showing micromolar affinity for FleA by isothermal titration calorimetry. The most potent derivative was co-crystallized with FleA to gain insights into the binding mode in operation. Its chemical multimerization on a cyclodextrin scaffold led to an hexavalent compound with a significantly enhanced binding affinity (Kd = 223 ± 21 nM) thanks to a chelate binding mode. The compound could probe the role of bronchial epithelial cells in a FleA-mediated response to tissue invasion
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https://hal.archives-ouvertes.fr/hal-03429198
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Submitted on : Monday, November 15, 2021 - 2:57:14 PM
Last modification on : Wednesday, April 27, 2022 - 3:53:13 AM
Long-term archiving on: : Wednesday, February 16, 2022 - 8:49:59 PM

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Christophe Dussouy, Pierre-Alban Lalys, Aurore Cabanettes, Victor Lehot, David Deniaud, et al.. Hexavalent thiofucosides to probe the role of the Aspergillus fumigatus lectin FleA in fungal pathogenicity. Organic and Biomolecular Chemistry, Royal Society of Chemistry, 2021, 19 (14), pp.3234-3240. ⟨10.1039/D1OB00152C⟩. ⟨hal-03429198⟩

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