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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-BasagoitiFábio Luís Lima MonteiroLauren R H KrumpeVictoria Armario-NajeraShilpa R ShenoyDaniel Perez-ZsoltHarrison James WestgarthGemma VillorbinaLarissa Maciel BomfimDàlia Raïch-ReguéLara NoguerasCurtis J HenrichMarçal GallemíFilipe Romero Rebello MoreiraPascual TorresJennifer WilsonMirela D'arcSilvia MarfilAlice Laschuk HerlingerEdwards PradenasLuiza Mendonça HigaManuel Portero-OtinBenjamin TrinitéRichard M TwymanTeresa CapellAmilcar TanuriJulian BlancoNuria Izquierdo-UserosElibio Leopoldo RechPaul ChristouBarry R O'Keefe
Published in: Proceedings of the National Academy of Sciences of the United States of America (2023)
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.
Keyphrases
  • sars cov
  • respiratory syndrome coronavirus
  • escherichia coli
  • binding protein
  • high resolution
  • cell death
  • gene expression
  • cancer therapy
  • oxidative stress
  • cell proliferation
  • genome wide
  • mass spectrometry
  • disease virus