Novel anti-hepatitis B virus flavonoids sakuranetin and velutin from Rhus retinorrhoea

Drug-resistance in hepatitis B virus (HBV), especially due to prolonged treatment with nucleoside analogs, such as lamivudine ( LAM), remains a clinical challenge. Alternatively, several plant products and isolated phytochemicals have been used as promising anti-HBV therapeutics with no sign of resistance. Among all known Rhus species, R. coriaria, R. succedanea and R. tripartite have been widely studied for their anti-HBV efficacy, however, the effects of R. retinorrhoea have not been previously investigated. The current study reported the isolation of two flavonoids, namely sakuranetin (SEK) and velutin ( VEL), from the dichloromethane fraction of R. retinorrhoea aerial parts using chromatography and spectral analyses. The two flavonoids (6.25-50 mu g/ml) were pre-tested for non-hepatocytotoxicity using an MTT assay and their dose- and time-dependent inhibitory activities against HBV [hepatitis B surface antigen (HBsAg) and hepatitis B 'e' antigen (HBeAg)] in cultured HepG2.2.15 cells were assessed by ELISA. SEK and VEL at the selected doses (12.5 mu g/ml) significantly inhibited HBsAg by similar to 58.8 and similar to 56.4%, respectively, and HBeAg by similar to 55.5 and similar to 52.4%, respectively, on day 5. The reference drugs LAM and quercetin (anti-HBV flavonoids), suppressed the production of HBsAg/HBeAg by similar to 86.4/similar to 64 and similar to 84.5/similar to 62%, respectively. Furthermore, molecular docking of the flavonoids with HBV polymerase and capsid proteins revealed the formation of stable complexes with good docking energies, thus supporting their structure-based antiviral mechanism. In conclusion, the present study was the first to demonstrate the anti-HBV therapeutic activities of SEK and VEL isolated from R. retinorrhoea.

Automated summary

This study isolated two flavonoids, Sakuranetin (SEK) and Velutin (VEL), from R. retinorrhoea and demonstrated their significant inhibitory activities against HBV. The two flavonoids were able to suppress the production of HBsAg and HBeAg in cultured HepG2.2.15 cells. Molecular docking analysis also revealed their stable interactions with HBV polymerase and capsid proteins, supporting their antiviral mechanism based on structure.