Researchers at the University of Texas at Austin have discovered how a certain drug is able to stop viral spread for patients with Hepatitis C, and the finding may have important implications for drug developers seeking to stop other RNA viruses, including the virus that causes COVID-19.
A new paper out today in the Journal of Biological Chemistry from Kenneth Johnson, a professor of molecular biosciences, describes how he and his team examined the biochemical mechanism that enables an antiviral drug called sofosbuvir to halt replication in the Hepatitis C virus. The drug, sold under the brand name Sovaldi, has been a gamechanger since its introduction in 2013 for many patients by effectively curing Hepatitis C, including in people who had fought the virus for years. But before now, scientists didn't know why it worked better than alternatives, only that it did.
"It was important to understand why this drug worked and why a very similar one did not because that guides our understanding of future drug discovery," Johnson said.
The study looked at two drugs, sofosbuvir and another drug candidate called mericitabine, both nucleotide analogs. This means the drugs mimic one of the four normal building blocks of RNA and are incorporated during RNA replication of the virus; in so doing, they essentially stop viral replication.
Despite having much in common with the other drug, sofosbuvir is known to be a far more effective drug for treating Hepatitis C infections. Johnson and his team discovered the reason: the RNA replication process has a built-in mechanism that effectively reverses inhibition by certain drugs, though not sofosbuvir.
When the RNA replication process came to sections coding for cytosine, mericitabine was introduced as a substitute for cytosine in the RNA molecules, but it was subsequently removed by the enzyme in less than a minute. But sofosbuvir stands in for a different base molecule called uracil, and this small difference was the key to getting the error past the natural proofreading system – as well as to understanding why one drug worked so much better.
It turns out that Hepatitis C, HIV and the coronavirus SARS-CoV-2 share similar structures and biochemical processes. With this new information about how viruses incorporate nucleotide analog drugs and how they combat some of those drugs more effectively, scientists have new insights for developing drugs to fight the other viruses.
Johnson started out in his work in this area studying DNA replication in bacteriophages, viruses that only attack bacteria. He then moved on to HIV, then Hepatitis C and now the novel coronavirus.
"It's exciting to work on Hepatitis C and coronavirus because there is an opportunity to do really good biochemistry and make fundamental discoveries, but which also have implications in healthcare," Johnson said. "Our work, and that of many others, demonstrates the value of basic research."
Brian Villalba of MoMa Therapeutics and Jiawen Li of Singular Genomics Systems contributed to the research. Funding for the research was provided by the National Institute of Allergies and Infectious Diseases and the Welch Foundation. Drug samples were provided by Janssen Pharmaceutical and Gilead Sciences. Johnson is president of KinTek Corporation, which provided an instrument and software used in the experiment.
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