Multivalent Fucosides with Nanomolar Affinity for the Aspergillus fumigatus Lectin FleA Prevent Spore Adhesion to Pneumocytes. Issue 72 (26th November 2018)

• Record Type: Journal Article
• Authors: Lehot, Victor; Brissonnet, Yoan; Dussouy, Christophe; Brument, Sami; Cabanettes, Aurore; Gillon, Emilie; Deniaud, David; Varrot, Annabelle; Le Pape, Patrice; Gouin, Sébastien G.
• Is Part Of: Chemistry. Volume 24:Issue 72(2018)
• Page Start: 19243
• Page End: 19249
• Publication Date: 2018-11-26
• Subjects: antifungal agents -- cell adhesion -- chelates -- glycoconjugates -- surface chemistry; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201803602
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: FleA (or AFL), a fucose lectin, was recently identified in the opportunistic mold Aspergillus fumigatus, which causes fatal lung infections in immunocompromised patients. We designed di‐, hexa‐ and octavalent fucosides with various spacer arm lengths to block the hexameric FleA through chelation. Microcalorimetry measurements showed that the ethylene glycol (EG) spacer arm length has a strong influence on the binding affinity of the divalent fucosides. The relationship between the EG length and chelate binding efficiency to FleA was explored according to polymer theory. Hexa‐ and octavalent compounds based on cyclodextrin and octameric silsesquioxane scaffolds were nanomolar FleA inhibitors, surpassing their monovalent fucose analogue by more than three orders of magnitude. Importantly, some of the fucosides were highly efficient in preventing fungal spore adhesion to bronchoepithelial cells, with half maximal inhibitory concentration values in the micromolar range. We propose that the synergistic antiadhesive effect observed can be ascribed to chelate binding to FleA and to the formation of conidium aggregates, as observed by optical microscopy. These fucosides are promising tools that can be used to better understand the role of FleA in conidia pathogenicity and host defenses against invasive aspergillosis. Abstract : Working together : FleA receptor in the opportunistic pathogen Aspergillus fumigatus was shown to be involved in spore (conidium) adherence to airway mucins and bronchoepithelial cells. We developed multivalent fucosides with various valencies and spacer arm lengths as conidium antiadhesives (see figure). The hexa‐ and octavalent fucosides were nanomolar antagonists of FleA, strongly inhibiting conidium adherence to pneumocytes.