Department of Functional Neuroanatomy, Institute for Anatomy and Cell Biology, Heidelberg University, Im Neuenheimer Feld 307, 69120, Heidelberg, Germany.
Department of Infectious Diseases, Molecular Virology, Heidelberg University, 69120, Heidelberg, Germany; German Center for Infection Research (DZIF), Partner Site Heidelberg, 69120, Heidelberg, Germany.
Antiviral Res. 2024 May;225:105856. doi: 10.1016/j.antiviral.2024.105856. Epub 2024 Mar 5.
Four years after its outbreak, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a global challenge for human health. At its surface, SARS-CoV-2 features numerous extensively glycosylated spike proteins. This glycan coat supports virion docking and entry into host cells and at the same time renders the virus less susceptible to neutralizing antibodies. Given the high genetic plasticity of SARS-CoV-2 and the rapid emergence of immune escape variants, targeting the glycan shield by carbohydrate-binding agents emerges as a promising strategy. However, the potential of carbohydrate-targeting reagents as viral inhibitors remains underexplored. Here, we tested seven plant-derived carbohydrate-binding proteins, called lectins, and one crude plant extract for their antiviral activity against SARS-CoV-2 in two types of human lung cells: A549 cells ectopically expressing the ACE2 receptor and Calu-3 cells. We identified three lectins and an Allium porrum (leek) extract inhibiting SARS-CoV-2 infection in both cell systems with selectivity indices (SI) ranging between >2 and >299. Amongst these, the lectin Concanavalin A (Con A) exerted the most potent and broad activity against a panel of SARS-CoV-2 variants. We used multiplex super-resolution microscopy to address lectin interactions with SARS-CoV-2 and its host cells. Notably, we discovered that Con A not only binds to SARS-CoV-2 virions and their host cells, but also causes SARS-CoV-2 aggregation. Thus, Con A exerts a dual mode-of-action comprising both, antiviral and virucidal, mechanisms. These results establish Con A and other plant lectins as candidates for COVID-19 prevention and basis for further drug development.
新冠病毒（SARS-CoV-2）爆发四年后，仍然是全球人类健康的一大挑战。SARS-CoV-2 的表面有许多广泛糖基化的刺突蛋白。这种糖涂层支持病毒粒子的对接和进入宿主细胞，同时使病毒对中和抗体的敏感性降低。鉴于 SARS-CoV-2 的高度遗传可塑性和免疫逃逸变异的快速出现，通过碳水化合物结合剂靶向糖衣被认为是一种很有前途的策略。然而，碳水化合物靶向试剂作为病毒抑制剂的潜力仍未得到充分探索。在这里，我们在两种类型的人肺细胞中测试了七种植物来源的碳水化合物结合蛋白，称为凝集素，以及一种粗植物提取物，以评估它们对 SARS-CoV-2 的抗病毒活性：过表达 ACE2 受体的 A549 细胞和 Calu-3 细胞。我们在这两种细胞系统中鉴定出三种凝集素和一种葱属植物（韭菜）提取物，对 SARS-CoV-2 感染具有抑制作用，其选择性指数（SI）在 2 到 299 之间。在这些中，凝集素伴刀豆球蛋白 A（Con A）对一组 SARS-CoV-2 变体表现出最强大和广泛的活性。我们使用多重超分辨率显微镜来研究凝集素与 SARS-CoV-2 及其宿主细胞的相互作用。值得注意的是，我们发现 Con A 不仅与 SARS-CoV-2 病毒粒子及其宿主细胞结合，而且还导致 SARS-CoV-2 聚集。因此，Con A 发挥了双重作用机制，包括抗病毒和病毒裂解作用。这些结果确立了 Con A 和其他植物凝集素作为 COVID-19 预防的候选物，并为进一步的药物开发奠定了基础。
