Researchers evaluate the potency of antiviral lectins against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) and SARS-CoV, thus illustrating its potential as a pan-coronavirus (CoV) inhibitor.
Study
In the present study, researchers evaluate three antiviral lectins, including griffithsin (GRFT), Oscillatoria agardhii agglutinin (OAA), and Burkholderia oklahomensis agglutinin (BOA), for their potential to inhibit Vero E6 cells infected with the wild-type SARS-CoV-2 strain.
The effectiveness of BOA was also evaluated against the SARS-CoV-2, Alpha, Beta, Gamma, Delta, and Omicron BA.1 VOCs, as this lectin exhibited the highest anti-SARS-CoV-2 activity. The in vitro binding of OAA and BOA to the SARS-CoV-2 S glycoprotein was also evaluated using size exclusion chromatography (SEC).
Dynamic light scattering (DLS) was used to characterize the OAA- and BOA-induced aggregation of S. Pseudoviruses expressing SARS-COV-2 S protein variants N234A and N165A (control) were also developed to explore the mechanism of action of BOA-induced SARS-CoV-2 entry.
Results
GRFT exhibited no activity in all three virus-neutralization systems, whereas BOA and OAA exhibited potent inhibitory activity. In plaque assays, BOA blocked the wild-type SARS-CoV-2 variant with a half maximal effective concentration (EC50) value of nine nanomolar nM.
Thus, GRFT is structurally distinct from OAA and BOA and binds to different substructures of high mannose glycans. Structurally, BOA and OAA vary in the number of glycan-binding sites and beta-barrel domains; however, both exhibit the same glycan specificities, which allows for similar mechanisms of inhibition between these lectins.
Since BOA has four glycan binding sites, which is twice that of OAA, it was a more potent inhibitor of SARS-CoV-2. In fact, removing three of the four sugar-binding sites on BOA eliminated its antiviral activity.
In biophysical assays, the researchers mixed equimolar amounts of lectin and S proteins. In 5:1 or 10:1 molar excess of OAA or BOA, additional elution peaks for S protein were observed, thus suggesting that this viral protein formed large molecular mass complexes with OAA and BOA. The interactions between soluble aggregates formed by BOA and SARS-CoV-2 S conferred antiviral activity upon BOA.
In vitro, a monovalent BOA variant bound to the SARS-CoV-2 S protein but did not form soluble aggregates, which prevented any antiviral activity. Thus, the potent inhibitory activity of BOA against SARS-CoV-2 can be attributed to its multivalent interactions, which reduce to monovalent contacts to ultimately inhibit the SARS-CoV-2.
Psuedovirus experiments suggested that N234 or its glycan was essential for SARS-CoV-2 entry into host cells. Similarly, one previous study reported that the 234 glycan was essential for the functioning of the SARS-CoV-2 S function.
Conclusion
SARS-CoV-2 variants exhibit minimal changes with respect to glycosylation, which allowed for BOA to consistently and potently inhibit all tested viral variants. The similar potency of BOA against SARS-CoV, which initially emerged in 2003, demonstrates that the activity of this lectin is dependent on S protein glycans rather than its specific sequence. These findings support developing future therapeutic strategies using multivalent glycan binders as pan-CoV inhibitors.
Source:
https://www.news-medical.net/news/20230914/Unlocking-the-power-of-lectins-BOA-emerges-as-a-potent-weapon-against-all-SARS-CoV-2-variants.aspx