Researchers have identified a weakness in viral enzymes that could lead to new treatments for a variety of diseases, including COVID-19 and Ebola. This approach aims to minimize side effects and lower the chances of developing drug resistance.
The introduction of Paxlovid in December 2021 marked a significant milestone in the COVID-19 pandemic, providing an effective antiviral that has benefited millions. However, like many other antivirals, it is anticipated that Paxlovid will eventually lose its effectiveness due to the emergence of drug resistance. Researchers are striving to combat such challenges and have discovered a brand-new method to treat SARS-CoV-2 infections, potentially influencing a range of viruses.
A recent study from the Tuschl lab presents a foundational concept for a new class of antivirals targeting an enzyme critical to not just SARS, but several RNA viruses including Ebola and dengue, as well as DNA viruses like Pox viruses. This research could enhance our ability to respond more quickly and effectively to future pandemics. “No one has previously found a way to inhibit this enzyme,” states Thomas Tuschl, a professor at Rockefeller University. “Our research positions cap methyl transferase enzymes as potential therapeutic targets, paving the way for further antiviral advancements against pathogens we have limited means to combat so far.”
A promising path ahead
RNA viruses often survive by altering their RNA caps—the structures that stabilize viral RNA, boost its translation, and imitate host mRNA, helping the virus to evade immune defenses. This capping process relies on enzymes called methyltransferases, making them attractive targets for antiviral medications.
Traditionally, most antivirals like Paxlovid have focused on disrupting proteases, another group of viral enzymes responsible for breaking down proteins. These enzymes have been targeted effectively in the past to prevent viral spread. “Inhibiting methyltransferase represented a unique challenge due to the need for a non-standard RNA substrate,” Tuschl explains.
As an expert in RNA, Tuschl’s prior experience has already led to the development of various RNA treatments for genetic conditions. When restructuring his lab to focus on developing antiviral drugs during the pandemic, he recognized benefits in targeting more than just protease inhibitors. Tuschl hypothesized that viruses would find it harder to evade a combination therapy that attacks two different viral enzymes simultaneously, such as a protease inhibitor along with a methyltransferase inhibitor. He also noted that drugs attacking viral methyltransferases could be designed very differently from human enzymes, ensuring selectivity and sparing human enzyme function.
To find a molecule that could inhibit the SARS-CoV-2 methyltransferase NSP14, Tuschl’s team screened 430,000 compounds early in the pandemic at the Fisher Drug Discovery Resource Center. This effort resulted in a handful of compounds that successfully inhibited NSP14, a multifunctional enzyme with methyltransferase capabilities.
These compounds underwent an extensive development process to create optimized drugs in partnership with the Sanders Tri-Institutional Therapeutics Discovery Institute. The most promising compounds were subjected to cell-based tests overseen by Charles M. Rice, who leads the Laboratory of Virology and Infectious Disease at Rockefeller. Subsequently, the potential treatments were tested in mice under BL3 safety conditions at the Center for Discovery and Innovation in New Jersey, demonstrating similar efficacy to Paxlovid in treating COVID-19. Furthermore, Tuschl and his team confirmed that the treatment remained effective even against virus mutations and showed synergy when used in combination with protease inhibitors.
“A virus would struggle to escape this compound on its own,” Tuschl asserts. “When used as part of a combined therapy with a protease inhibitor, evasion would be nearly impossible.”
Returning to fundamentals
The study not only highlights the potential of viral methyltransferases as valuable therapeutic targets, but it also indicates that Tuschl’s specific inhibitor is likely to cause minimal side effects. “The mechanism of action for this drug is distinct,” he adds. The compound leverages unique structural features of the viral methyltransferase, requiring the presence of the methyl donor SAM, which means the lab’s compound specifically targets the virus without interfering with human biological processes.
“We’re not yet ready for human testing,” Tuschl warns. A suitable clinical candidate needs enhancements in stability, bioavailability, and various other pharmacological properties that require long-term optimization. “We’re an academic lab, and for that, we would need a partner in the industry.”
Looking ahead, the Tuschl lab plans to expand its research to identify inhibitors for RSV, flaviviruses like dengue and Zika, mpox, and even certain fungal infections, all of which share similar vulnerabilities in their enzymatic functions. “This study opens opportunities to target multiple pathogens,” he remarks. “It presents a new chance to prepare for potential future pandemics.”
