Department of Chemistry, Stanford University, Stanford, CA, 94305, USA.
Department of Bioengineering, University of Utah, Salt Lake City, UT, 84112, USA.
Angew Chem Int Ed Engl. 2018 Mar 12;57(12):3137-3142. doi: 10.1002/anie.201713075. Epub 2018 Feb 21.
The C-type lectins dectin-1 and dectin-2 contribute to innate immunity against microbial pathogens by recognizing their foreign glycan structures. These receptors are promising targets for vaccine development and cancer immunotherapy. However, currently available agonists are heterogeneous glycoconjugates and polysaccharides from natural sources. Herein, we designed and synthesized the first chemically defined ligands for dectin-1 and dectin-2. They comprised glycopolypeptides bearing mono-, di-, and trisaccharides and were built through polymerization of glycosylated N-carboxyanhydrides. Through this approach, we achieved glycopolypeptides with high molecular weights and low dispersities. We identified structures that elicit a pro-inflammatory response through dectin-1 or dectin-2 in antigen-presenting cells. With their native proteinaceous backbones and natural glycosidic linkages, these agonists are attractive for translational applications.
C 型凝集素 dectin-1 和 dectin-2 通过识别其外源糖基结构有助于先天免疫抵抗微生物病原体。这些受体是疫苗开发和癌症免疫治疗的有前途的靶点。然而，目前可用的激动剂是异质糖缀合物和天然来源的多糖。在此，我们设计并合成了 dectin-1 和 dectin-2 的首个化学定义配体。它们由带有单糖、二糖和三糖的糖肽组成，通过糖基化 N-羧酸酐的聚合来构建。通过这种方法，我们实现了具有高分子量和低分散性的糖肽。我们鉴定了通过抗原呈递细胞中的 dectin-1 或 dectin-2 引发炎症反应的结构。由于它们具有天然的蛋白质骨架和天然的糖苷键，这些激动剂非常适合转化应用。
