2. Academic Validation
  3. Junceellolide B, a novel inhibitor of Hepatitis B virus

Junceellolide B, a novel inhibitor of Hepatitis B virus

  • Bioorg Med Chem. 2020 Aug 15;28(16):115603. doi: 10.1016/j.bmc.2020.115603.
Xiaodan Li 1,  Hui Liu 2,  Wei Cheng 1,  Jie Wang 2,  He Zhang 1,  Fengmin Lu 3,  Xiangmei Chen 4,  Wenhan Lin 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, PR China.
  • 2 Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing 100191, PR China.
  • 3 State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, PR China; Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing 100191, PR China.
  • 4 Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing 100191, PR China. Electronic address: xm_chen6176@bjmu.edu.cn.
  • 5 State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, PR China; Institute of Ocean Research, Peking University, Beijing 100875, PR China. Electronic address: whlin@bjmu.edu.cn.
PMID: 32690259 DOI: 10.1016/j.bmc.2020.115603
Abstract

HBV Infection is a common cause of liver disease with a high burden worldwide. Current therapeutic strategy relies on interferon and nucleos(t)ide-type drugs with the limitation of functional cure. In this study, a structure-based screening of Marine natural products from an in-house library was performed to hit HBV inhibitors, and the gorgonian-derived briarane-type Diterpenoids showed inhibitory effects against HBV DNA replication in HepAD38 cells. Preliminary analyses of structure-activity relationship demonstrated that a briarane-based scaffold with an 3E,5(16)-diene and a chlorine-substitution at C-6 is required for the anti-HBV activity. Junceellolide B is one of the potent HBV inhibitors exhibiting efficient reduction of HBsAg and HBeAg production in HBV infected HepG2-NTCP cells with a dose-dependent manner (p < 0.001). It also significantly reduced the secreted HBV DNA, HBV RNA, and HBeAg in HepAD38 cells with the EC50 values of 0.83, 2.87 and 7.75 μM, respectively. Mechanistically, junceellolide B potently inhibited HBV RNA transcription without promoting HBV RNA degradation. RNA-seq analysis indicated that junceellolide B significantly decreased HBV cccDNA-transcripted products accompanying stable down-regulation of the expression of RNA polymerase II related host transcription factors (ZBED6 and ZBTB7B). These findings suggest junceellolide B to be a transcription inhibitor of cccDNA and a promising lead for the development of new anti-HBV agent.

Keywords

Briarane-type diterpenoids; Hepatitis B virus; Junceellolide B; Marine natural products; cccDNA.

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