Dynamic Cooperative Glycan Assembly Blocks the Binding of Bacterial Lectins to Epithelial Cells

Abstract

Pathogens frequently rely on lectins for adhesion and cellular entry into the host. Since these interactions typically result from multimeric binding of lectins to cell-surface glycans, novel therapeutic strategies are being developed with the use of glycomimetics as competitors of such interactions. Herein we study the benefit of nucleic acid based oligomeric assemblies with PNA-fucose conjugates. We demonstrate that the interactions of a lectin with epithelial cells can be inhibited with conjugates that do not form stable assemblies in solution but benefit from cooperativity between ligand-protein interactions and PNA hybridization to achieve high affinity. A dynamic dimeric assembly fully blocked the binding of the fucose-binding lectin BambL of Burkholderia ambifaria, a pathogenic bacterium, to epithelial cells with an efficiency of more than 700-fold compared to l-fucose.

Architecture and Evolution of Blade Assembly in β-propeller Lectins

“…Since some of them are involved in host-pathogen recognition, they are also promising targets for glycomimetic compounds that could present anti-infectious properties. Designing multivalent molecules that fit the specific binding sites arrangement of β-propellers in pathogenic micro-organisms has been key to obtain high-affinity inhibitors (Goyard et al, 2018;(Jancarikova et al, 2018;(Machida et al, 2017). Because of their ability to bind strongly to glycoconjugates on cell surfaces, PropLecs are also useful biomarkers, for probing the glycosylation of proteins (Liu et al, 2018;(Machon et al, 2017), for labelling cancer cells (Audfray et al, 2015), or as tools to study the dynamics of glycolipids in membranes (Arnaud et al, 2013).…”

Applying Multivalent Biomolecular Interactions for Biosensors

“…[10] As ynthetically prepared oligomeric PNA-fucose conjugate exhibited as ubnanomolar affinity against ap athogenic lectin protein, representing more than a 1000-fold increase from af ucose monomer. [11] This oligomeric fucose inhibited pathogenic bacterium infection on epithelial cells over700-fold more effectively than monomeric fucose.…”

“…[19] DNA or PNA based architectures have provided versatile scaffolds for multivalentb iomolecular display. [11,20] Valency and ligand spacing can be precisely controlled on these nucleic acid structures, although DNA-ligand conjugation is necessary. For instance, aDNA/ligand-PNA system that provides well-controlledl igand density and valency was used to precisely characterizem ultivalent GPCR-ligandi nteractions.…”

A Multivalent Structure‐Specific RNA Binder with Extremely Stable Target Binding but Reduced Interaction with Nonspecific RNAs

“…Multivalency can also be an influential concept for biosensing as the binding characteristics between target biomolecules and receptor probes are major determining factors for sensing ability. Multiple studies have demonstrated that increased valency can strengthen binding affinities by several orders of magnitude, potentially offering nearly irreversible binding stability of receptor probes against target molecules ,. However, there is a general concern that even weak interactions between receptor probes and other nonspecific molecules can be also enhanced by multivalency.…”