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Inhibition of hepatitis B virus replication by targeting ribonucleotide reductase M2 protein

Xia Liu1, Zhijian Xu2, Chuanwei Hou2

  • 1Department of Pathology and Pathophysiology, Key Laboratory of Disease Proteomics of Zhejiang Province, Research Center for Air Pollution and Health, Zhejiang University School of Medicine, Hangzhou 310058, China; Central Laboratory, The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China.

Biochemical Pharmacology
|January 18, 2016
PubMed

Insights

Ribonucleotide reductase (RR) is vital for hepatitis B virus (HBV) replication. The compound osalmid effectively inhibits RR, reducing HBV DNA and cccDNA synthesis, offering a new treatment strategy for hepatitis B and related liver cancer.

Area of Science:

  • Hepatology
  • Virology
  • Drug Discovery

Background:

  • Chronic hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC).
  • Ribonucleotide reductase (RR) is crucial for DNA synthesis and a target for anti-cancer therapies.
  • RR's role in HBV replication and HBV covalently-closed-circular DNA (cccDNA) synthesis is not well understood.

Purpose of the Study:

  • To investigate the role of RR in HBV replication.
  • To identify and evaluate novel RR inhibitors as potential anti-HBV agents.
  • To explore the therapeutic potential of osalmid and its derivatives against HBV infection and drug-resistant strains.

Main Methods:

  • Computer-assisted virtual screening to identify RRM2 inhibitors.
  • In vitro assays to assess RR inhibitory activity and HBV replication inhibition.
  • Cell-based assays using HepG2.2.15 cells to evaluate HBV DNA and cccDNA synthesis.
  • Testing against 3TC-resistant HBV strains.
  • In vivo studies to confirm osalmid's efficacy and safety.

Main Results:

  • Osalmid, identified via virtual screening, potently inhibits RR activity, surpassing hydroxyurea.
  • Osalmid significantly reduces HBV DNA and cccDNA synthesis in vitro.
  • Osalmid demonstrates activity against 3TC-resistant HBV strains and synergistic effects with lamivudine (3TC).
  • A novel derivative, YZ51, exhibits enhanced efficacy and RR inhibitory activity compared to osalmid.
  • Osalmid inhibits RR activity in vivo, confirming its functional role.

Conclusions:

  • RR, specifically RRM2, is essential for HBV replication and cccDNA formation.
  • Osalmid is a potent RRM2 inhibitor with significant anti-HBV activity, including against resistant strains.
  • Osalmid and its derivative YZ51 represent a promising new class of anti-HBV therapeutics for hepatitis B and HBV-related HCC.
Keywords:
Drug synergism and drug resistanceHepatitis B virusHuman ribonucleotide reductase small subunit M2 (RRM2)Small molecule compoundsViral genomic DNA and cccDNA synthesis

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