Scientists discover key to hepatitis A replication

pharmafile | July 8, 2022 | News story | Medical Communications  

UNC School of Medicine scientists discovered the key to hepatitis A virus (HAV) replication. They also found an oral compound which at a key juncture stops viral replication of HAV, 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 HAV in an animal model of the disease.

The researchers discovered that the oral compound RG7834 stopped replication at a key step, also finding that HAV replication requires specific interactions between the human protein ZCCHC14, and a group of enzymes called TENT4 poly(A) polymerases.

“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 senior author Stanley M Lemon, MD, professor in the UNC Department of Medicine and UNC Department of Microbiology & Immunology, and member of the UNC Institute for Global Health and Infectious Diseases.

The viral replication cycle is crucial for a virus to spread inside the body and cause disease. In 2013, Lemon and colleagues discovered that the hepatitis A virus changes dramatically inside the human liver. The researchers found that HAV hijacks portions of cell membrane as it exits liver cells, thereby evading antibodies that would have otherwise quarantined the virus before it spread widely through the blood stream. Now, the team has found that HAV hijacks TENT4 and uses it to replicate its own genome.

“We found ZCCHC14 binds very specifically to a certain part of HAV’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,” explained Lemon.

“This compound is a long way from human use,” Lemon concluded, “But it points the path to an effective way to treat a disease for which we have no treatment at all.” “The treatment for Hepatitis A would be short term, and, more importantly, our group and others are working on compounds that would hit the same target without toxic effects.”

Ana Ovey

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