New SARS-CoV-2 variants are continuously emerging with critical implications for therapies or vaccinations. The 22 N-glycan sites of Spike remain highly conserved among SARS-CoV-2 variants, opening an avenue for robust therapeutic intervention. Here we used a comprehensive library of mammalian carbohydrate-binding proteins (lectins) to probe critical sugar residues on the full-length trimeric Spike and the receptor binding domain (RBD) of SARS-CoV-2. Two lectins, Clec4g and CD209c, were identified to strongly bind to Spike. Clec4g and CD209c binding to Spike was dissected and visualized in real time and at single-molecule resolution using atomic force microscopy. 3D modelling showed that both lectins can bind to a glycan within the RBD-ACE2 interface and thus interferes with Spike binding to cell surfaces. Importantly, Clec4g and CD209c significantly reduced SARS-CoV-2 infections. These data report the first extensive map and 3D structural modelling of lectin-Spike interactions and uncovers candidate receptors involved in Spike binding and SARS-CoV-2 infections. The capacity of CLEC4G and mCD209c lectins to block SARS-CoV-2 viral entry holds promise for pan-variant therapeutic interventions.

中文翻译：

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鉴定保守 SARS-CoV-2 糖基化位点的凝集素受体

新的 SARS-CoV-2 变体不断出现，对治疗或疫苗接种具有重要意义。22N _-Spike 的聚糖位点在 SARS-CoV-2 变体中保持高度保守，为强有力的治疗干预开辟了道路。在这里，我们使用了一个综合的哺乳动物碳水化合物结合蛋白（凝集素）文库来探测 SARS-CoV-2 的全长三聚体刺突和受体结合域 (RBD) 上的关键糖残基。两种凝集素 Clec4g 和 CD209c 被鉴定为与 Spike 强烈结合。Clec4g 和 CD209c 与 Spike 的结合使用原子力显微镜以单分子分辨率实时解剖和可视化。3D 建模表明，两种凝集素都可以与 RBD-ACE2 界面内的聚糖结合，从而干扰刺突与细胞表面的结合。重要的是，Clec4g 和 CD209c 显着减少了 SARS-CoV-2 感染。这些数据报告了凝集素-Spike 相互作用的第一个广泛图谱和 3D 结构模型，并揭示了参与 Spike 结合和 SARS-CoV-2 感染的候选受体。CLEC4G 和 mCD209c 凝集素阻断 SARS-CoV-2 病毒进入的能力为泛变异治疗干预带来了希望。