Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 59, Issue 47, Pages 21016-21022Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202006880
Keywords
carbohydrate recognition; DNA nanotechnology; lectins; multivalent interactions; peptide nucleic acids
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Funding
- Deutsche Forschungsgemeinschaft [SFB 765]
- Max-Planck Society
- Projekt DEAL
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Binders of langerin could target vaccines to Langerhans cells for improved therapeutic effect. Since langerin has low affinity for monovalent glycan ligands, highly multivalent presentation has previously been key for targeting. Aiming to reduce the amount of ligand required, we rationally designed molecularly defined high-affinity binders based on the precise display of glycomimetic ligands (Glc2NTs) on DNA-PNA scaffolds. Rather than mimicking langerin's homotrimeric structure with a C3-symmetric scaffold, we developed readily accessible, easy-to-design bivalent binders. The method considers the requirements for bridging sugar binding sites and statistical rebinding as a means to both strengthen the interactions at single binding sites and amplify the avidity enhancement provided by chelation. This gave a 1150-fold net improvement over the affinity of the free ligand and provided a nanomolar binder (IC50=300 nM) for specific internalization by langerin-expressing cells.
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