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Abstract
Multivalent structures displaying different instead of similar sugar units, namely heteroglycoclusters (hGCs), are stimulating the efforts of glycochemists for developing compounds with new biological properties. Here we report a four-step strategy to synthesize hexadecavalent hGCs displaying eight copies of αFuc and βGal. These compounds were tested for the binding to lectins LecA and LecB from Pseudomonas aeruginosa. While parent fucosylated (19) and galactosylated (20) homoclusters present nanomolar affinity with LecB and LecA, respectively, we observed that hGCs combining these sugars (11 and 13) maintain their binding potency with both lectins despite the presence of an unspecific sugar. The added multivalency is therefore not a barrier for efficient recognition by bacterial receptors and it opens the route for adding different sugars that can be selected for their immunomodulatory properties.
Highlights
Glycoclusters and glycodendrimers remain a growing source of interest in glycosciences (Renaudet and Roy, 2013)
In the course of developing multivalent glycoconjugates (Galan et al, 2013; Daskhan et al, 2015), we recently focused on the synthesis of a variety of cyclopeptide-based hGCs using orthogonal chemoselective conjugation methods such as the oxime ligation (OL), the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC), and the thiol-ene, thiol-chloroactetyl and diethyl squarate couplings (TEC, TCC, DSC)
We described a series of homovalent glycodendrimers with nanomolar affinity for LecB (Berthet et al, 2013)
Summary
Glycoclusters and glycodendrimers remain a growing source of interest in glycosciences (Renaudet and Roy, 2013). Synthetic chemists focused their efforts on structures displaying multiple copies of a single sugar unit to both clarify and modulate biological and pathological processes involving multivalent interactions with proteins (Bernardi et al, 2013; Cecioni et al, 2015; Arsiwala et al, 2019) These compounds only partially reflect the heterogeneous expression of glycans at the cell surface (i.e., glycocalyx) and completely underestimate that other sugar units may participate or promote additional biological events (Jiménez Blanco et al, 2013; Müller et al, 2016). Because αMan is ligand of LecB, though with a lower affinity than αFuc, we synthesized different combinations of hGCs containing this residue to evaluate its potential influence in the binding to these two lectins
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