Cyanovirin-N binds to select SARS-CoV-2 spike oligosaccharides outside of the receptor binding domain and blocks infection by SARS-CoV-2

Jordana Muñoz-Basagoiti, Fábio Luís Lima Monteiro, Lauren R.H. Krumpe, Victoria Armario-Najera, Shilpa R. Shenoy, Daniel Perez-Zsolt, Harrison James Westgarth, Gemma Villorbina, Larissa Maciel Bomfim, Dàlia Raïch-Regué, Lara Nogueras, Curtis J. Henrich, Marçal Gallemí, Filipe Romero Rebello Moreira, Pascual Torres, Jennifer Wilson, Mirela D’arc, Silvia Marfil, Alice Laschuk Herlinger, Edwards PradenasLuiza Mendonça Higa, Manuel Portero-Otin, Benjamin Trinité, Richard M. Twyman, Teresa Capell, Amilcar Tanuri, Julià Blanco, Nuria Izquierdo-Useros, Elibio L. Rech, Paul Christou, Barry R. O’Keefec

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Resum

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an enveloped positive stranded RNA virus which has caused the recent deadly pandemic called COVID-19. The SARS-CoV-2 virion is coated with a heavily glycosylated Spike glycoprotein which is responsible for attachment and entry into target cells. One, as yet unexploited strategy for preventing SARS-CoV-2 infections, is the targeting of the glycans on Spike. Lectins are carbohydrate-binding proteins produced by plants, algae, and cyanobacteria. Some lectins can neutralize enveloped viruses displaying external glycoproteins, offering an alternative therapeutic approach for the prevention of infection with virulent β-coronaviruses, such as SARS-CoV-2. Here we show that the cyanobacterial lectin cyanovirin-N (CV-N) can selectively target SARS-CoV-2 Spike oligosaccharides and inhibit SARS-CoV-2 infection in vitro and in vivo. CV-N neutralizes Delta and Omicron variants in vitro better than earlier circulating viral variants. CV-N binds selectively to Spike with a Kd as low as 15 nM and a stoichiometry of 2 CV-N: 1 Spike but does not bind to the receptor binding domain (RBD). Further mapping of CV-N binding sites on Spike shows that select high-mannose oligosaccharides in the S1 domain of Spike are targeted by CV-N. CV-N also reduced viral loads in the nares and lungs in vivo to protect hamsters against a lethal viral challenge. In summary, we present an anti-coronavirus agent that works by an unexploited mechanism and prevents infection by a broad range of SARS-CoV-2 strains.

Idioma originalAnglès
Número d’articlee2214561120
Nombre de pàgines12
RevistaProceedings of the National Academy of Sciences of the United States of America
Volum120
Número10
DOIs
Estat de la publicacióPublicada - 7 de març 2023
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