Multivalent carbohydrate-based ligands
were synthesized and evaluated
as inhibitors of the adhesion protein HA of the influenza A virus
(IAV). HA relies on multivalency for strong viral adhesion. While
viral adhesion inhibition by large polymeric molecules has proven
viable, limited success was reached for smaller multivalent compounds.
By linking of sialylated LAcNAc units to di- and trivalent scaffolds,
inhibitors were obtained with an up to 428-fold enhanced inhibition
in various assays.
Cholera is a potentially
fatal bacterial infection that affects
a large number of people in developing countries. It is caused by
the cholera toxin (CT), an AB5 toxin secreted by Vibrio cholera. The toxin comprises a toxic A-subunit
and a pentameric B-subunit that bind to the intestinal cell surface.
Several monovalent and multivalent inhibitors of the toxin have been
synthesized but are too complicated and expensive for practical use
in developing countries. Meta-nitrophenyl α-galactoside (MNPG)
is a known promising ligand for CT, and here mono- and multivalent
compounds based on MNPG were synthesized. We present the synthesis
of MNPG in greatly improved yields and its use while linked to a multivalent
scaffold. We used economical polymers as multivalent scaffolds, namely,
polyacrylamide, dextran, and hyperbranched polyglycerols (hPGs). Copper-catalyzed
alkyne azide cycloaddition reaction (CuAAC) produced the inhibitors
that were tested in an ELISA-type assay and an intestinal organoid
swelling inhibition assay. The inhibitory properties varied widely
depending on the type of polymer, and the most potent conjugates showed
IC50 values in the nanomolar range.
Fungi have provided us with life-changing small bioactive molecules, with the best-known examples being the first broad-spectrum antibiotic penicillin, immunosuppressive cyclosporine, and cholesterol-lowering statins. Since the 1980s, exploration of chemical diversity in nature has been highly reduced.
Thermoresponsive receptors for the recognition unit of the cholera toxin (CTB) can recognise the protein with nanomolar affinity. An increase in temperature can drastically reduce their avidity, enabling on-demand release of CTB.
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