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Cross Talk between Nucleotide Synthesis Pathways with Cellular Immunity in Constraining Hepatitis E Virus

Yijin Wang1, Wenshi Wang1, Lei Xu1

  • 1Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.

Antimicrobial Agents and Chemotherapy
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PubMed
Summary

This study explores how different steps in nucleotide biosynthesis affect the replication of hepatitis E virus (HEV). Researchers found that inhibiting later steps in the purine pathway, especially targeting IMP dehydrogenase (IMPDH), strongly reduces HEV replication. In contrast, early step inhibitors enhance replication. Pyrimidine pathway inhibitors also show strong antiviral effects. These inhibitors trigger the expression of antiviral genes, even without the usual interferon signaling pathway. The findings suggest that targeting specific enzymes in nucleotide synthesis could lead to new antiviral drugs for HEV. This is important because there are currently no FDA-approved treatments for HEV.

Keywords:
nucleotide biosynthesishepatitis E virusantiviral drug developmentinterferon-stimulated genes

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Area of Science:

  • Viral replication mechanisms in virology
  • Metabolic pathway regulation in pharmacology

Background:

Understanding virus-host interactions is crucial for developing antiviral therapies. De novo nucleotide biosynthesis supports both host metabolism and viral replication. Prior research has shown that enzymes in these pathways may serve as antiviral targets. However, the specific roles of nucleotide synthesis in viral replication remain unclear. This gap motivated the investigation of how different enzymatic steps in nucleotide biosynthesis influence hepatitis E virus (HEV) replication. No prior work had resolved whether early or late steps in purine synthesis are more effective for antiviral activity. The lack of FDA-approved anti-HEV drugs highlights the need for alternative therapeutic strategies. This study aims to clarify the relationship between nucleotide biosynthesis and HEV replication. The findings could provide insights into novel antiviral approaches. The role of interferon-stimulated genes in this context has not been fully explored.

Purpose Of The Study:

This study aimed to explore the role of nucleotide biosynthesis pathways in HEV replication. The specific problem addressed is the lack of FDA-approved antiviral drugs for HEV. The motivation stems from the need to identify new therapeutic targets. The researchers focused on how different enzymatic steps in nucleotide synthesis affect HEV replication. They sought to determine whether early or late steps in purine biosynthesis are more effective for antiviral activity. The study also examined the impact of pyrimidine pathway inhibition on HEV. The goal was to assess whether these inhibitors trigger antiviral gene expression. Understanding these mechanisms could lead to novel antiviral strategies.

Main Methods:

The study used pharmacological inhibitors of nucleotide biosynthesis to assess their effects on HEV replication. Researchers tested inhibitors targeting early and late steps of the purine synthesis pathway. They also evaluated inhibitors of the pyrimidine synthesis pathway. The replication levels of HEV were measured in cell culture models. The expression of interferon-stimulated genes (ISGs) was monitored to assess antiviral activity. The JAK-STAT pathway was examined to determine if ISG induction was dependent on interferons. The study compared the antiviral efficacy of different inhibitors. The findings were analyzed to identify the most effective targets for HEV inhibition.

Main Results:

Inhibiting the later steps of purine biosynthesis significantly reduced HEV replication. In contrast, early step inhibitors enhanced HEV replication. Pyrimidine pathway inhibitors also showed strong antiviral activity. The most effective target in the purine pathway was IMP dehydrogenase (IMPDH). Clinically used IMPDH inhibitors, such as mycophenolic acid and ribavirin, exhibited potent anti-HEV effects. These inhibitors induced the expression of interferon-stimulated genes (ISGs). The ISG induction occurred independently of the classical JAK-STAT pathway. The results suggest that nucleotide synthesis pathway inhibitors can counteract HEV replication through unconventional mechanisms.

Conclusions:

The study revealed an unconventional mechanism linking nucleotide biosynthesis and cellular antiviral immunity. Targeting specific enzymes in nucleotide synthesis pathways can inhibit HEV replication. The most effective target in the purine pathway is IMP dehydrogenase. Pyrimidine pathway inhibitors also show strong antiviral activity. The antiviral effects of these inhibitors depend on the induction of interferon-stimulated genes. This induction occurs independently of the JAK-STAT pathway. The findings suggest that nucleotide synthesis pathway inhibitors represent viable antiviral drug candidates. These results provide a foundation for developing new therapies against HEV.

The study shows that these inhibitors trigger antiviral interferon-stimulated genes (ISGs) independently of the JAK-STAT pathway.

IMPDH (IMP dehydrogenase) is the most important anti-HEV target in the purine synthesis pathway.

Later step inhibitors, like those targeting IMPDH, reduce HEV replication, while early step inhibitors enhance it.

ISGs are induced by nucleotide synthesis inhibitors, contributing to antiviral activity without JAK-STAT pathway involvement.

Yes, mycophenolic acid and ribavirin, which inhibit IMPDH, show potent anti-HEV activity.

The study suggests that targeting nucleotide synthesis enzymes could lead to new therapies for HEV.