Bhat Sajad Ahmad, Hasan Syed Kazim, Parray Zahoor Ahmad, Siddiqui Zaheenul Islam, Ansari Shabnam, Anwer Ayesha, Khan Saniya, Amir Fatima, Mehmankhah Mahboubeh, Islam Asimul, Minuchehr Zarrin, Kazim Syed Naqui
Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, 110025, India.
Department of Biotechnology, Jamia Millia Islamia, New Delhi, India.
Gut Pathog. 2023 Mar 9;15(1):11. doi: 10.1186/s13099-023-00531-6.
Interferon and nucleos(t)ide analogues are current therapeutic treatments for chronic Hepatitis B virus (HBV) infection with the limitations of a functional cure. Chrysin (5, 7-dihydroxyflavone) is a natural flavonoid, known for its antiviral and hepatoprotective activities. However, its anti-HBV activity is unexplored.
In the present study, the anti-hepatitis B activity of chrysin was investigated using the in vitro experimental cell culture model, HepG2 cells. In silico studies were performed where chrysin and lamivudine (used here as a positive control) were docked with high mobility group box 1 protein (HMGB1). For the in vitro studies, wild type HBV genome construct (pHBV 1.3X) was transiently transfected in HepG2. In culture supernatant samples, HBV surface antigen (HBsAg) and Hepatitis B e antigen (HBeAg) were measured by enzyme-linked immunosorbent assay (ELISA). Secreted HBV DNA and intracellular covalently closed circular DNA (cccDNA) were measured by SYBR green real-time PCR. The 3D crystal structure of HMGB1 (1AAB) protein was developed and docked with the chrysin and lamivudine. In silico drug-likeness, Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) properties of finest ligands were performed by using SwissADME and admetSAR web servers.
Data showed that chrysin significantly decreases HBeAg, HBsAg secretion, supernatant HBV DNA and cccDNA, in a dose dependent manner. The docking studies demonstrated HMGB1 as an important target for chrysin as compared to lamivudine. Chrysin revealed high binding affinity and formed a firm kissing complex with HMGB1 (∆G = - 5.7 kcal/mol), as compared to lamivudine (∆G = - 4.3 kcal/mol), which might be responsible for its antiviral activity.
The outcome of our study establishes chrysin as a new antiviral against HBV infection. However, using chrysin to treat chronic HBV disease needs further endorsement and optimization by in vivo studies in animal models.
干扰素和核苷（酸）类似物是目前治疗慢性乙型肝炎病毒（HBV）感染的方法，但存在功能性治愈方面的局限性。白杨素（5,7 - 二羟基黄酮）是一种天然黄酮类化合物，以其抗病毒和肝脏保护活性而闻名。然而，其抗HBV活性尚未得到研究。
在本研究中，使用体外实验细胞培养模型HepG2细胞研究了白杨素的抗乙型肝炎活性。进行了计算机模拟研究，将白杨素和拉米夫定（此处用作阳性对照）与高迁移率族蛋白B1（HMGB1）进行对接。对于体外研究，将野生型HBV基因组构建体（pHBV 1.3X）瞬时转染到HepG2细胞中。在培养上清液样本中，通过酶联免疫吸附测定（ELISA）测量HBV表面抗原（HBsAg）和乙型肝炎e抗原（HBeAg）。通过SYBR绿实时PCR测量分泌的HBV DNA和细胞内共价闭合环状DNA（cccDNA）。开发了HMGB1（1AAB）蛋白的三维晶体结构，并将其与白杨素和拉米夫定进行对接。使用SwissADME和admetSAR网络服务器对白杨素和拉米夫定这两种最佳配体进行计算机模拟药物相似性、吸收、分布、代谢、排泄和毒性（ADMET）特性分析。
数据显示，白杨素以剂量依赖性方式显著降低HBeAg、HBsAg分泌、上清液HBV DNA和cccDNA。对接研究表明，与拉米夫定相比，HMGB1是白杨素的重要靶点。与拉米夫定（∆G = - 4.3 kcal/mol）相比，白杨素显示出高结合亲和力，并与HMGB1形成了牢固的亲吻复合物（∆G = - 5.7 kcal/mol），这可能是其抗病毒活性的原因。
我们的研究结果确立了白杨素作为一种抗HBV感染的新型抗病毒药物。然而，使用白杨素治疗慢性HBV疾病需要在动物模型中进行体内研究进一步验证和优化。
