Quercetin inhibits SARS-CoV-2 infection and prevents syncytium formation by cells co-expressing the viral spike protein and human ACE2
Annie V Roy, Michael Chan, Logan Banadyga, Shihua He, Wenjun Zhu, Michel Chrétien, Majambu Mbikay
Virology Journal, doi:10.1186/s12985-024-02299-w
Background Several in silico studies have determined that quercetin, a plant flavonol, could bind with strong affinity and low free energy to SARS-CoV-2 proteins involved in viral entry and replication, suggesting it could block infection of human cells by the virus. In the present study, we examined the ex vivo ability of quercetin to inhibit of SARS-CoV-2 replication and explored the mechanisms of this inhibition. Methods Green monkey kidney Vero E6 cells and in human colon carcinoma Caco-2 cells were infected with SARS-CoV-2 and incubated in presence of quercetin; the amount of replicated viral RNA was measured in spent media by RT-qPCR. Since the formation of syncytia is a mechanism of SARS-CoV-2 propagation, a syncytialization model was set up using human embryonic kidney HEK293 co-expressing SARS-CoV-2 Spike (S) protein and human angiotensin converting enzyme 2 (ACE2), [HEK293(S + ACE2) cells], to assess the effect of quercetin on this cytopathic event by microscopic imaging and protein immunoblotting.
Results Quercetin inhibited SARS-CoV-2 replication in Vero E6 cells and Caco-2 cells in a concentration-dependent manner with a half inhibitory concentration (IC 50 ) of 166.6 and 145.2 µM, respectively. It also inhibited syncytialization of HEK293(S + ACE2) cells with an IC 50 of 156.7 µM. Spike and ACE2 co-expression was associated with decreased expression, increased proteolytic processing of the S protein, and diminished production of the fusogenic S2' fragment of S. Furin, a proposed protease for this processing, was inhibited by quercetin in vitro with an IC 50 of 116 µM.
Conclusion These findings suggest that at low 3-digit micromolar concentrations of quercetin could impair SARS-CoV-2 infection of human cells partly by blocking the fusion process that promotes its propagation.
Abbreviations
Supplementary Information The online version contains supplementary material available at https://doi. org/10.1186/s12985-024-02299-w. Supplementary Material 1: Supplementary Figure S1 . Confirmation of S protein bands. Cells were transfected with the indicated expression vectors and their extracts analyzed as described for Fig. 3 . Immunoblotting of S protein and its fragments was performed using antibodies from Abcam (cat# ab272504) and Sino Biological (cat# 40592-T62). The Spike-Linker-GFP gene is expressed as a fusion S-GFP protein whereas with the Spike-P2A-GFP gene, the S protein and GFP are expressed as two separate molecules, hence the size difference in immunoreactive S bands produced par the two vectors. Supplementary Material 2: Supplementary Figure S2 . Pull-down of ACE2 by S protein. HEK293(S+ACE2) cell extracts were subjected to immunoprecipitation with GFP-trap beads. The precipitates were analyzed by immunoblotting for ACE-2 and GFP; the densities of immunoreactive bands were determined. A. A representative blot. B&C. The S/ACE2 and S2/ACE density ratios were computed. The values (means ± SD of 3 independent experiments) of quercetin-treated cells were expressed relative to those of DMSO treated control cells. Supplementary Material 3: Supplementary Figure S3 . Effect of isoquercetin on HEK293(S+ACE2) syncytialization. The experiment was conducted as described in Fig. 1 . Isoquercetin did not inhibit the formation de syncytia...
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