Apilimod blocked hepatitis E virus entry into cells — News-Medical

The PIKfyve inhibitor apilimod blocked the entry of hepatitis E virus (HEV) into cells in laboratory experiments and also reduced viral RNA levels in some tissues of rats infected with ratHEV. As reported by News-Medical, the results were published in the journal eGastroenterology.

Hepatitis E virus is one of the leading causes of acute viral hepatitis. Available antiviral treatment is largely limited to the off-label use of ribavirin. This drug can have substantial toxicity, is contraindicated during pregnancy, and does not help all patients.

A target in the cell

The researchers tested compounds that affect endocytic and endolysosomal pathways, an intracellular transport system that HEV uses during cell entry. Apilimod, which inhibits the phosphoinositide kinase PIKfyve, showed the strongest effect. In HepG2/C3A cells, the drug was active at nanomolar concentrations.

Inhibition of PIKfyve using small interfering RNAs reduced HEV infection by approximately 40%. Two other inhibitors of this enzyme, YM201636 and APY0201, also suppressed infection. The effect was observed for quasi-enveloped and non-enveloped viral particles, as well as for different HEV strains.

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Effect on lysosomes

Experiments showed that blocking PIKfyve disrupts the delivery of HEV genomes to late endosomes and lysosomes. Apilimod also reduced the maturation and activity of cathepsins B and L, lysosomal proteases that researchers believe are involved in processing the viral capsid and releasing its genome into the cytoplasm.

Apilimod reduced infection of primary human hepatocytes without a corresponding reduction in cell viability, although higher concentrations were required than in hepatoma cell lines. Rats were given the drug at a dose of 75 mg/kg once daily for 12 days. Treatment altered the dynamics of viral shedding in feces, but the reduction in overall viral load by this measure did not reach the conventional level of statistical significance.

The authors emphasize that the findings are preclinical. Further studies must determine safe therapeutic concentrations, tissue toxicity, activity against other HEV genotypes, and efficacy in chronic or already established infection.