Introducing affinity and selectivity into galectin-targeting nanoparticles with fluorinated glycan ligands

Abstract

A chemo-enzymatic site-specific fluorination strategy is employed to obtain glyco-nanoparticles with tuneable selectivity towards galectins.

Selectively Deoxyfluorinated N‐Acetyllactosamine Analogues as 19F NMR Probes to Study Carbohydrate‐Galectin Interactions

“…Selected structures of deoxyfluorinated lacto-N-biose analogues conjugated to PHEA coated gold nanoparticles and the binding affinities of the resulting multivalent systems to Gal-3 and Gal-7 expressed as K d . [16] PHEA = poly(hydroxyethyl acrylamide). ND = observed affinity was too low to be determined.…”

“…Gal-3 has also been recently probed with nanoparticles carrying deoxyfluorinated lacto-N-biose and the 6'-position has been confirmed as critical because deoxyfluorination at C6' abolished binding. [16] The introduction of a highly polar CÀ F bond can strengthen noncovalent ligand-protein interaction for example via electrostatic and dipolar interactions with cationic residues (e. g. the guanidinium group) and protein backbone or side-chain amide groups. [60] While this strategy to improve affinity of protein ligands was generally exceptionally fruitful, including galectin ligands fluorinated at aryl substituents [13,61] or polyfluorinated carbohydrates, [62] mono-deoxyfluorinated oligosaccharides typically display similar, attenuated or abrogated affinity to lectins in comparison with the natural ligands.…”

“…Recent results with lacto-N-biose analogues highlight the potential of the multivalent display of fluorinated sugars to identify highly potent and/or selective inhibitors. [16]…”

“…Very weak binding of 6 , 7 and 8 to Gal‐3 determined by ELISA was also corroborated by NMR from a relative increase in R 2 values upon addition of galectins (Figure 5), underscoring the utility of this NMR method for sensitive screening of ligand‐galectin interactions. Gal‐3 has also been recently probed with nanoparticles carrying deoxyfluorinated lacto‐ N ‐biose and the 6′‐position has been confirmed as critical because deoxyfluorination at C6′ abolished binding [16] …”

“…reported on the chemoenzymatic synthesis of a series of deoxyfluorinated lacto‐ N ‐biose analogues and their immobilization on PHEA (poly(hydroxyethyl acrylamide)) coated gold nanoparticles (Figure 1). [16] The analogue 2 deoxyfluorinated at the 3‐position of the galacto moiety showed an enhanced affinity to Gal‐3 and Gal‐7 in comparison with the non‐fluorinated ligand 1 , whereas the analogue 3 , deoxyfluorinated at the 6‐position of the galacto moiety displayed abrogated binding to both Gal‐3 and Gal‐7. Importantly, multiply fluorinated LacNAc analogue 4 showed reversal of the selectivity in comparison with the non‐fluorinated standard 1 , strongly favoring binding to Gal‐7 over Gal‐3, which highlighted deoxyfluorination as a promising strategy in the development of selective galectin inhibitors.…”