Department of Chemistry, Humboldt-Universität zu Berlin, 12489, Berlin, Germany.
Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, 14424, Potsdam, Germany.
Angew Chem Int Ed Engl. 2020 Nov 16;59(47):21016-21022. doi: 10.1002/anie.202006880. Epub 2020 Sep 15.
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 =300 nM) for specific internalization by langerin-expressing cells.
langerin 的结合物可以将疫苗靶向朗格汉斯细胞，以提高治疗效果。由于 langerin 与单价糖基配体的亲和力低，因此以前高度多价的呈递是靶向的关键。为了减少所需配体的数量，我们基于糖基模拟物配体（Glc2NTs）在 DNA-PNA 支架上的精确展示，合理设计了分子定义的高亲和力结合物。我们没有用 C3 对称支架来模拟 langerin 的三聚体结构，而是开发了易于获得、易于设计的二价结合物。该方法考虑了桥连糖结合位点的要求和统计再结合，既是为了增强单个结合位点的相互作用，也是为了放大螯合提供的亲和增强。与游离配体相比，这使亲和力提高了 1150 倍，为表达 langerin 的细胞的特异性内化提供了一种纳摩尔结合物（IC =300 nM）。
