Rational Design of a DNA-Scaffolded High-Affinity Binder for Langerin.
Rational Design of a DNA-Scaffolded High-Affinity Binder for Langerin.
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Langerin的DNA支架高亲和力结合剂的合理设计。
DOI：
10.1002/anie.202006880
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发表时间：
2020-11-16
期刊：
影响因子：
--
通讯作者：
Seitz O
中科院分区：
文献类型：
--
作者：
Bachem G;Wamhoff EC;Silberreis K;Kim D;Baukmann H;Fuchsberger F;Dernedde J;Rademacher C;Seitz O
Langerin的结合剂可以将疫苗靶向Langerhans细胞以提高治疗效果。由于langerin对单价聚糖配体具有低亲和力，因此高度多价呈递先前是靶向的关键。为了减少所需配体的量，我们基于拟糖配体（Glc 2NTs）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剂。我们没有用C3对称支架模拟langerin的同源三聚体结构，而是开发了易于获得，易于设计的二价结合剂。该方法考虑了桥接糖结合位点和统计再结合的要求，作为加强单个结合位点处的相互作用和放大螯合作用提供的亲合力增强的手段。这使游离配体的亲和力净提高了1150倍，并为表达langerin的细胞的特异性内化提供了纳摩尔结合剂（IC 50 =300 nM）。 统计再结合和螯合物结合相互加强，并协同增加对多价靶标的亲和力。在刚性PNA-DNA支架上的两个糖模拟化合物的小簇的距离限定展示提供了C型凝集素受体langerin的第一个分子限定的纳摩尔结合剂。高亲和力结合剂被langerin表达细胞选择性内化。
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. Statistical rebinding and chelate binding reinforce each other and cooperatively increase the affinity for a multivalent target. The distance‐defined display of two small clusters of a glycomimetic compound on a rigid PNA‐DNA scaffold provided the first molecularly defined, nanomolar binder of the C‐type lectin receptor langerin. The high‐affinity binders are selectively internalized by langerin‐expressing cells.
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