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Rational Design of a DNA‐Scaffolded High‐Affinity Binder for Langerin
Author(s) -
Bachem Gunnar,
Wamhoff EikeChristian,
Silberreis Kim,
Kim Dongyoon,
Baukmann Hannes,
Fuchsberger Felix,
Dernedde Jens,
Rademacher Christoph,
Seitz Oliver
Publication year - 2020
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202006880
Subject(s) - langerin , avidity , chemistry , internalization , glycan , nanocarriers , biophysics , ligand (biochemistry) , escher , dna , nanotechnology , combinatorial chemistry , computational biology , biochemistry , computer science , materials science , biology , receptor , dendritic cell , antigen , drug delivery , immunology , organic chemistry , glycoprotein , programming language
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 (IC 50 =300 nM) for specific internalization by langerin‐expressing cells.