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.