New York: US scientists have discovered how a protein and enzymes interact to allow the hepatitis A virus to replicate. They also used a known drug to stop viral replication in an animal model.
While there is vaccination available for hepatitis A virus, there are currently no treatments for the disease that can exist for long periods of time in the environment, such as on our hands and in food and water.
Globally, tens of millions of hepatitis A infections occur each year. Symptoms include fever, abdominal pain, jaundice, nausea, and loss of appetite and sense of taste.
The team from University of North Carolina discovered that replication requires specific interactions between the human protein ZCCHC14, a protein that interacts with zinc and binds to RNA, and a group of enzymes called TENT4 poly(A) polymerases.
They also found 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 Proceedings of the National Academy of Sciences, are the first to demonstrate an effective drug treatment against hepatitis A in an animal model of the disease.
“Our research demonstrates that targeting this protein complex with an orally delivered, small-molecule therapeutic halts 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 outbreak settings,” said Stanley M. Lemon, Professor in the University’s Department of Medicine.
“We found ZCCHC14 binds very specifically to a certain part of hepatitis A’s RNA, the molecule that contains the virus’s genetic information. And as a result of that binding, the virus is able to recruit TENT4 from the human cell,” he added.
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.
The study suggested that stopping TENT4 recruitment could stop viral replication and limit disease.
The team then tested the compound RG7834, and found that the oral compound dramatically diminished the virus’s ability to cause liver injury in mice that had been genetically modified to develop hepatitis A infection and disease.
The research suggests the compound was safe at the dose used in this study.
While “this compound is a long way from human use”, Lemon said, “it points the path to an effective way to treat a disease for which we have no treatment at all”.