Fluoro-Fucosylation Enables the Interrogation of the Lea – LecB Interaction by BioNMR Spectroscopy

Abstract

Fucosylation patterns in cell-surface glycans are essential mediators of recognition and signalling. Aberrations in these signatures serve as vital diagnostic markers of disease progression, and so understanding fucose-protein interactions at the molecular level is crucial. Molecular editing of l-fucose (Fuc) at C2 with fluorine provides a platform to reconcile the ubiquity of fucosylation with the paucity of strategies to interrogate site-specific interactions. Through judicious introduction of a pseudo-equatorial fluorine [C(sp3)-F] adjacent to the anomeric position, β-selective fucosylation can be achieved with a range of diverse acceptors (>50:1): the selectivity of this process can be inverted through changes in the donor scaffold. Reaction development was driven by the desire to construct a fluorinated analogue of Lewis antigen a (F-Lea), in which fluorine replaces a key OH group at C2. Lea is a ligand for Lectin B (LecB) in the pathogen Pseudomonas aeruginosa and thus delineating the importance of key interactions in this complex has ramifications for drug discovery. Independent syntheses of Lea and F-Lea, and systematic bioNMR analyses with both glycans has unequivocally established the essential role of O2 of fucose in the Lea-LecB complex.