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-Nájera, Shilpa R. Shenoy, Daniel Perez‐Zsolt, Harrison James Westgarth, Gemma Villorbina, Larissa Bomfim, Dàlia Raϊch‐Regué, Lara Nogueras, Curtis J. Henrich, Marçal Gallemí, Filipe Romero Rebello Moreira, Pascual Torres, Jennifer A. Wilson, Mirela D’arc, Sílvia Marfil, Alice Laschuk Herlinger, Edwards Pradenas, Luiza M. Higa, Manuel Portero‐Otín, Benjamin Trinité, Richard M. Twyman, Teresa Capell, Amílcar Tanuri, Julià Blanco, Nuria Izquierdo‐Useros, Elíbio Rech, Paul Christou, Barry R. O’Keefe
Abstract
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.