Antiviral medications such as oseltamivir (Tamiflu) are currently used to treat flu symptoms and sometimes given preventively to people at high risk for the flu and related complications. But there have been questions about the effectiveness of oseltamivir, and the World Health Organization (WHO) removed the drug from its list of essential medicines in June 2017, downgrading it from a “core” drug to one that is “complementary” or less cost-effective. Research presented March 19 at the National Meeting and Exposition of the American Chemical Society in New Orleans points to a different kind of antiviral medication that could more effectively stop H3 viruses. “There is a lot of interest in this product,” says Seth Cohen, PhD, the lead author of the study. “It’s a good opportunity to help individuals who are particularly susceptible to flu infection: the elderly, the young, and the immuno-compromised.”
Targeting How a Virus Replicates
Researchers at the University of California in San Diego identified a vulnerability in the structure of the influenza virus that could be targeted in treatment. The flu shot is less effective against H3 because these viruses are more likely to mutate after the vaccine has been produced — something referred to as the H3 flaw. Many bacteria and viruses rely on target host cells’ own DNA to replicate. But influenza relies on its own enzyme, called RNA polymerase. This enzyme is categorized as a metalloenzyme because it is dependent on manganese metal ions to replicate. More than 30 percent of known enzymes are metalloenzymes. The RNA polymerase complex remains constant across many different versions and mutations of the influenza virus, according to Dr. Cohen. So therapies that target it are not likely to fail due to the H3 flaw that plagues existing vaccines. Cohen and his team developed a small-molecule drug and made some minor tweaks to it that enabled the drug to bind to the manganese ions and thereby shut down the virus’s ability to replicate and infect cells throughout the body — a process known as metalloenzyme inhibitor technology. “The modification dramatically improved the potency of the compound over previous drugs we created,” says Cohen, who is the cofounder of Forge Therapeutics, a San Diego–based biotechnology company that develops drugs that target metalloenzymes. “We knew it would be simple to add just a few atoms. Even a small tweak, adding a few atoms, could enhance the activity by a factor of 1,000.” Targeting metalloenzymes is an approach that’s being pursued by other pharmaceutical companies developing antiviral medications, Cohen says. “This is becoming routine in these viral therapeutics. I’m happy to see other companies are validating this target.” Future studies will examine whether this small molecule is able to slow down the virus or stop it completely from replicating and mutating.
