CHAPEL HILL, N.C. – Scientists have discovered a drug that may hold the key to curing hepatitis A.
A team from the UNC School of Medicine found that the virus needs specific interactions between the human protein ZCCHC14 and a group of enzymes called TENT4 poly(A) polymerases in order to replicate. With that knowledge in hand, they successfully tested the oral drug RG7834 on mice. The treatment not only stopped the hepatitis A virus (HAV) from replicating, but also made it impossible for HAV to infect liver cells.
Researchers say this is the first drug to deliver effective results in animals with HAV. Although a vaccine against the virus has been available for several years, there is currently no way of treating hepatitis A once someone has it.
“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,” says senior author Stanley M. Lemon, MD, professor in the UNC Department of Medicine and UNC Department of Microbiology & Immunology, in a university release.
‘It’s like comparing apples to turnips’
Lemon has been working on a treatment for hepatitis for decades. In the 1970s and 80s, the researcher was part of the Walter Reed Army Medical Center team which created the first inactivated HAV vaccine for humans.
Once the vaccine became widely available, cases of the virus dropped off in the mid-1990s. By the 2000s, cases of HAV plummeted as vaccination rates climbed higher.
With their success, researchers turned to treating hepatitis B and C, but Lemon says these viruses are extremely different from HAV — even though they share the same name. In fact, hepatitis A isn’t even part of the same virus family, according to researchers.
“It’s like comparing apples to turnips,” the study author explains. “The only similarity is that they all cause inflammation of the liver.”
Unfortunately, the team says hepatitis A has been making a comeback in recent years. Although the vaccine continues to be effective, cases have been rising since 2016, with the CDC recording more than 44,000 cases, 27,000 hospitalizations, and 400 deaths in the U.S. alone during that time.
Part of the problem is that not everyone gets vaccinated, and the virus can live in the environment for a long time — on people’s hands, on food, and in water.
Researchers say a 2017 outbreak in San Diego was largely driven by local homelessness and illicit drug use. Health officials traced a 2019 outbreak to contaminated blackberries and a 2022 outbreak to organic strawberries in several states.
What makes hepatitis A so hard to treat?
Globally, doctors diagnose millions of HAV infections each year. The virus causes fever, abdominal pain, jaundice, nausea, and a loss of appetite and sense of taste.
In 2013, Lemon and other researchers discovered that hepatitis A undergoes an extreme transformation once it reaches the liver. The virus hijacks parts of the cell membrane when it leaves the organ, making it invisible to antibodies that would normally attack and quarantine hepatitis A before it spreads through the blood.
A few years later, scientists discovered that hepatitis B needed TENT4A/B in order to replicate in patients. That discovery led other scientists to look for the human proteins HAV needs to replicate. Ultimately, the new study found ZCCHC14, a protein which interacts with zinc and binds to a person’s RNA.
“This was the tipping point for this current study,” Lemon explains. “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.”
The study author adds that, in a healthy person, TENT4 plays a role in RNA modification during cell growth. In people with hepatitis A, the virus hijacks TENT4 and uses it to reproduce. Researchers theorized that stopping the virus from hijacking TENT4 could limit HAV’s spread.
‘This compound is a long way from human use’
With previous studies showing that RG7834 can block hepatitis B from targeting TENT4, the team tested this compound on mice genetically engineered to have HAV. Results show oral treatments of RG7834 “dramatically diminished” liver injury in the animals. The dosage researchers used was also safe for the mice, but study authors add that they’re still far off from human trials.
“This compound is a long way from human use,” Lemon cautions, “but it points the path to an effective way to treat a disease for which we have no treatment at all.”
Previous animal studies testing RG7834 for use against chronic cases of hepatitis B suggested that the drug may be too toxic to use over a long period of time. However, Lemon says the short timeframe patients would need the drug for in order to treat HAV could avoid this side-effect.
“The treatment for Hepatitis A would be short term,” Lemon concludes, “and, more importantly, our group and others are working on compounds that would hit the same target without toxic effects.”
The study is published in the Proceedings of the National Academy of Sciences.