Bovine milk glycoproteins inhibit SARS-CoV-2 and influenza virus co-infection

The attachment of S1 subunit of spike (S) protein to angiotensin-converting enzyme 2 (ACE2) is the first and crucial step of SARS-CoV-2 infection. Although S protein and ACE2 are heavily glycosylated, the precise roles of glycans in their interactions are still unclear. Here, we profiled the glycopatterns of S1 subunit of SARS-CoV-2 and ACE2, and found that the galactosylated glycoforms were dominant in both S1 subunit and ACE2. Interestingly, S1 subunit exhibited the property of glycan-binding protein (GBP) and adhered to the ACE2 via binding to the galactosylated glycans on the ACE2. Our earlier findings demonstrated that the sialylated glycoproteins isolated from bovine milk potently inhibit and neutralize viral activity against influenza A virus (IAV). Importantly, we proved further that the galactosylated glycans on isolated glycoproteins bind to the glycan recognition domains of S1 subunit and competitively inhibit binding of S1 subunit to ACE2 and ultimately impede the entry of SARS-CoV-2 pseudovirus into host cells. We provided a potential protein drug that could be multiple simultaneous inhibitor for coronavirus and IAV co-infection.