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Journal Article

Rational design of an DNA-scaffolded high-affinity binder for langerin

MPS-Authors
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Wamhoff,  Eike-Christian
Christoph Rademacher, Biomolekulare Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society;

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Kim,  Dongyoon
Christoph Rademacher, Biomolekulare Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society;

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Baukmann,  Hannes
Christoph Rademacher, Biomolekulare Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society;

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Fuchsberger,  Felix F.
Christoph Rademacher, Biomolekulare Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society;

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Rademacher,  Christoph
Christoph Rademacher, Biomolekulare Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society;

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Citation

Bachem, G., Wamhoff, E.-C., Silberreis, K., Kim, D., Baukmann, H., Fuchsberger, F. F., et al. (2020). Rational design of an DNA-scaffolded high-affinity binder for langerin. Angewandte Chemie International Edition, 59(47), 21016-21022. doi:10.1002/anie.202006880.


Cite as: http://hdl.handle.net/21.11116/0000-0006-D2EA-5
Abstract
Binders of Langerin could target vaccines to Langerhans cells for improved therapeutic effect. As Langerin has only low affinity for monovalent glycan ligands, highly multivalent presentation has previously been key for targeting. Aiming to reduce the amount of ligands 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-symmetrical scaffold, we devised a strategy to improve 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. The method enabled 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.