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.
Hepatitis A Virus Replication
“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”.
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