Rational Design of a DNA-Scaffolded High-Affinity Binder for Langerin |
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| Authors: | Gunnar Bachem Dr. Eike-Christian Wamhoff Dr. Kim Silberreis Dr. Dongyoon Kim Hannes Baukmann Felix Fuchsberger Dr. Jens Dernedde Dr. Christoph Rademacher Prof. Oliver Seitz |
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| Affiliation: | 1. Department of Chemistry, Humboldt-Universität zu Berlin, 12489 Berlin, Germany;2. Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, 14424 Potsdam, Germany;3. Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 13353 Berlin, Germany |
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| Abstract: | 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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| Keywords: | carbohydrate recognition DNA nanotechnology lectins multivalent interactions peptide nucleic acids |
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