Mutations in spike (S) protein epitopes allow SARS-CoV-2
variants
to evade antibody responses induced by infection and/or vaccination.
In contrast, mutations in glycosylation sites across SARS-CoV-2 variants
are very rare, making glycans a potential robust target for developing
antivirals. However, this target has not been adequately exploited
for SARS-CoV-2, mostly due to intrinsically weak monovalent protein–glycan
interactions. We hypothesize that polyvalent nano-lectins with flexibly
linked carbohydrate recognition domains (CRDs) can adjust their relative
positions and bind multivalently to S protein glycans, potentially
exerting potent antiviral activity. Herein, we displayed the CRDs
of DC-SIGN, a dendritic cell lectin known to bind to diverse viruses,
polyvalently onto 13 nm gold nanoparticles (named G13-CRD). G13-CRD
bound strongly and specifically to target glycan-coated quantum dots
with sub-nMKd. Moreover, G13-CRD neutralized
particles pseudotyped with the S proteins of Wuhan Hu-1, B.1, Delta
variant and Omicron subvariant BA.1 with low nM EC50. In
contrast, natural tetrameric DC-SIGN and its G13 conjugate were ineffective.
Further, G13-CRD potently inhibited authentic SARS-CoV-2 B.1 and BA.1,
with <10 pM and <10 nM EC50, respectively. These
results identify G13-CRD as the 1st polyvalent nano-lectin with broad
activity against SARS-CoV-2 variants that merits further exploration
as a novel approach to antiviral therapy.