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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been transmitted across all over the world, in contrast to the limited epidemic of genetically- and virologically-related SARS-CoV. However, the molecular basis explaining the difference in the virological characteristics among SARS-CoV-2 and SARS-CoV has been poorly defined. Here we identified that host sialoglycans play a significant role in the efficient spread of SARS-CoV-2 infection, while this was not the case with SARS-CoV. SARS-CoV-2 infection was significantly inhibited by α2-6-linked sialic acid-containing compounds, but not by α2–3 analog, in VeroE6/TMPRSS2 cells. The α2-6-linked compound bound to SARS-CoV-2 spike S1 subunit to competitively inhibit SARS-CoV-2 attachment to cells. Enzymatic removal of cell surface sialic acids impaired the interaction between SARS-CoV-2 spike and angiotensin-converting enzyme 2 (ACE2), and suppressed the efficient spread of SARS-CoV-2 infection over time, in contrast to its least effect on SARS-CoV spread. Our study provides a novel molecular basis of SARS-CoV-2 infection which illustrates the distinctive characteristics from SARS-CoV. Author summary SARS-CoV-2, which has been highly transmissible and rapidly spreading worldwide, has caused approximately 458 million confirmed cases of COVID-19 with more than 6 million deaths by March 2022. Here we found that SARS-CoV-2 infection was significantly inhibited by α2-6-linked sialic acid-containing compounds and by depletion of cell surface sialic acid with only a minor effect on SARS-CoV infection. We identified that SARS-CoV-2 spike S1 subunit directly binds to α2-6-linked sialoglycans for efficient attachment to host cell surface. Our finding indicated that host sialoglycans play a significant role in the efficient infection of SARS-CoV-2, which provides a novel understanding of the molecular basis explaining the rapid spread of SARS-CoV-2 over SARS-CoV.