Inhibition of hepatitis B virus activities by <em>Rhazya stricta</em>‑derived acacetin and acetyl‑β‑carboline

Parvez,Mohammad K.; Alhowiriny,Tawfeq A.; Al-Dosari,Mohammed S.; Amina,Musarat; Rehman,Md Tabish; Al-Yousef,Hanan M.; Alanzi,Abdullah R.; Alajmi,Mohammed F.

doi:10.3892/etm.2023.12026

Inhibition of hepatitis B virus activities by Rhazya stricta‑derived acacetin and acetyl‑β‑carboline

Authors:
- Mohammad K. Parvez
- Tawfeq A. Alhowiriny
- Mohammed S. Al-Dosari
- Musarat Amina
- Md Tabish Rehman
- Hanan M. Al-Yousef
- Abdullah R. Alanzi
- Mohammed F. Alajmi
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Affiliations: Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Kingdom of Saudi Arabia
Published online on: May 16, 2023 https://doi.org/10.3892/etm.2023.12026
Article Number: 327

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Abstract

Hepatitis B virus (HBV) causes acute and chronic liver diseases, leading to cirrhosis and hepatocellular carcinoma. Although direct‑acting nucleoside analogs, such as lamivudine (LAM), adefovir and famciclovir, are available, emergence of drug‑resistance due to mutations in HBV polymerase (POL) restricts their further use. Alternatively, numerous plant products and compounds isolated from plants have been reported to confer anti‑HBV efficacies without any sign of resistance in vitro or in vivo. As, flavonoids and alkaloids are the most widely reported antivirals, the anti‑HBV activities of the flavonoid acacetin (ACT) and the alkaloid acetyl‑β‑carboline (ABC) from the aerial parts of Rhazya stricta were assessed in the present study. Both compounds were isolated from the ethyl acetate fraction of the total methanol extract using column and thin‑layer chromatography, and their structures were determined by nuclear magnetic resonance spectroscopy (NMR). Both compounds (at 6.25‑50 µg/ml) showed a lack of hepatocytotoxicity in cultured HepG2.2.15 cells. Anti‑HBV ELISA [hepatitis B surface antigen (HBsAg) and hepatitis B pre-core‑antigen (HBeAg)] on HepG.2.2.15 cells following treatment with selected concentrations (12.5, 25 and 50 µg/ml) of both compounds showed dose‑ and time‑dependent anti‑HBV activities. Compared with those in the untreated control at day 5, ACT and ABC (25 µg/ml, each) maximally inhibited HBsAg synthesis by 43.4 and 48.7%, respectively, whilst also maximally inhibiting HBeAg synthesis by 41.2 and 44.2%, respectively, in HepG2.2.15 cells. Comparatively, quercetin and LAM (standards; POL inhibitors) suppressed HBsAg (63.9 and 60.2%, respectively) and HBeAg synthesis (87.1 and 84.3%, respectively) by larger magnitudes. Molecular docking of ACT and ABC structures performed in AutoDock revealed their hydrogen bonding with the drug‑sensitive [wild‑type (wt)‑POL] ‘Tyr‑Met‑Asp‑Asp’ motif, in addition to the drug‑resistant [mutant (mut)‑POL] ‘Tyr‑Ile‑Asp‑Asp’ motif residues of the polymerase binding‑pocket, along with other electrostatic interactions. In the wt‑POL complex, both compounds showed good interactions with Asp205. In the mut‑POL complex, ACT and ABC interacted with Tyr203‑Asp205 and Tyr203‑Ile204, respectively. In conclusion, to the best of our knowledge, the present study demonstrates anti‑HBV efficacies of ACT and ABC in vitro for the first time, endorsed by in silico data. However, further molecular and pharmacological studies are required to validate their pre‑clinical therapeutic potential.

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