The SARS-CoV-2 virus spike protein complex (S) that is required for host cell infection is substantially covered by post-translationally added glycans (1, 2), as depicted in Figure and Table . Here, we asked the extent to which the function of S could be suppressed by lectins specific for glycans bearing terminal mannose residues . We found that the multivalent lectins CV-N and GRFT not only inhibited host cell infection by the Wuhan variant of SARS-CoV-2 pseudovirus by targeting Spike, but also caused irreversible inactivation of the virus. In contrast, the monovalent lectin MVN showed no inhibition of SARS-CoV-2, as opposed to the known MVN infection neutralization observed with HIV-1 pseudoviruses . Irreversible inactivation of SARS-CoV-2 pseudovirus was observed upon repeated lectin washout after treatment, which notably did not induce S1 shedding as a potential mechanism for the irreversible inactivation observed with lectins, as might have been analogous to the irreversible inactivation of HIV .