PT - JOURNAL ARTICLE AU - David Hoffmann AU - Stefan Mereiter AU - Yoo Jin Oh AU - Vanessa Monteil AU - Rong Zhu AU - Daniel Canena AU - Lisa Hain AU - Elisabeth Laurent AU - Clemens Grünwald-Gruber AU - Maria Novatchkova AU - Melita Ticevic AU - Antoine Chabloz AU - Gerald Wirnsberger AU - Astrid Hagelkruys AU - Friedrich Altmann AU - Lukas Mach AU - Johannes Stadlmann AU - Chris Oostenbrink AU - Ali Mirazimi AU - Peter Hinterdorfer AU - Josef M. Penninger TI - Identification of lectin receptors for conserved SARS-CoV-2 glycosylation sites AID - 10.1101/2021.04.01.438087 DP - 2021 Jan 01 TA - bioRxiv PG - 2021.04.01.438087 4099 - http://biorxiv.org/content/early/2021/04/01/2021.04.01.438087.short 4100 - http://biorxiv.org/content/early/2021/04/01/2021.04.01.438087.full AB - New SARS-CoV-2 variants are continuously emerging with critical implications for therapies or vaccinations. All 22 N-glycan sites of SARS-CoV-2 Spike remain highly conserved among the variants B.1.1.7, 501Y.V2 and P.1, 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.