An oral compound RG7834 is able to stop replication at a key step, making it impossible for the virus to infect liver cells
The viral replication cycle is crucial for a virus to spread within the body and cause disease. Focusing on that cycle in the hepatitis A virus (HAV), scientists at the University of North Carolina School of Medicine found that replication requires specific interactions between the human protein ZCCHC14 and a group of enzymes called TENT4 poly(A) polymerases.
They have also seen that the oral compound RG7834 stopped replication at a key step, making it impossible for the virus to infect liver cells.
These findings, published in the journal « Proceedings of the National Academy of Sciences », are the first to present an effective pharmacological treatment against HAV in an animal model of the disease.
‘Our research shows that targeting this protein complex with an orally administered molecule stops viral replication and reverses liver inflammation in a mouse model of hepatitis A providing proof of principle for antiviral therapy and the means to stop the spread of hepatitis A in outbreaks,” said lead author Stanley M. Lemon.
Lemon, who in the 1970s and 1980s was part of a research team at the Walter Reed Army Medical Center who developed the first inactivated HAV vaccine administered to humans, notes that HAV research dwindled after the vaccine became widely available in the mid-1990s.
Hepatitis A outbreaks have been on the rise since 2016, despite the highly effective HAV vaccine
Cases plummeted in the 2000s as vaccination rates soared. The researchers turned their attention to hepatitis B and C viruses, which are very different from HAV and cause chronic disease.
However, hepatitis A outbreaks have been on the rise since 2016, despite the highly effective HAV vaccine.
In 2013, Lemon and colleagues discovered that the hepatitis A virus changes drastically inside the human liver. The virus sequesters bits of the cell membrane as it exits liver cells, cloaking itself from antibodies that would otherwise have quarantined the virus before it spread widely through the bloodstream. This work was published in « Nature » and provided information on how much researchers still had to learn about this virus that was discovered 50 years ago and has probably caused diseases that date back to ancient times.
A few years ago, researchers discovered that the hepatitis B virus required TENT4A/B for its replication. Meanwhile, Lemon’s lab conducted experiments to look for human proteins HAV needs to replicate and found ZCCHC14, a particular protein that interacts with zinc and binds to RNA.
“This was the turning point for this current study,” Lemon acknowledges. We found that ZCCHC14 binds to a certain part of the HAV RNA, the molecule that contains the genetic information of the virus. And as a result of that binding, the virus can recruit TENT4 from the human cell.”
Although this compound is a long way from human use, it points the way to an effective way to treat a disease for which we have no treatment.
In normal human biology, TENT4 is part of an RNA modification process during cell growth. Essentially, HAV hijacks TENT4 and uses it to replicate its own genome.
This work suggested that stopping TENT4 recruitment could stop viral replication and limit disease. Lemon’s lab tested the compound RG7834, which had previously been shown to actively block the hepatitis B virus by targeting TENT4.
Although this compound is a long way from human use, Lemon notes, “it points the way to an effective way to treat a disease for which we have no treatment.”
Pharmaceutical company Hoffmann-La Roche developed RG7834 for use against chronic hepatitis B infections and tested it in humans in a phase 1 trial, but animal studies suggested it may be too toxic for use over long periods of time .
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