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The arrival of Paxlovid in December 2021 marked a significant turning point in the COVID-19 pandemic, offering an effective antiviral treatment that has since benefited millions. However, like many antivirals before it, Paxlovid faces the eventual challenge of drug resistance. Researchers aiming to stay ahead of such threats have now identified a novel method to treat SARS-CoV-2 infections—potentially leading to broader applications.
A recent study from the Tuschl laboratory has introduced a proof-of-concept for a new class of antivirals targeting a type of enzyme essential to SARS-CoV-2, many RNA viruses (including Ebola and dengue), and cytosolic-replicating DNA viruses (including Pox viruses). These findings, published in the journal Nature, could pave the way for a faster and more robust response to future pandemics.
“Nobody has found a way to inhibit this enzyme before,” said Thomas Tuschl, F. M. Al Akl and Margaret Al Akl professor at Rockefeller University. “Our work establishes cap methyl transferase enzymes as therapeutic targets and opens the door to many more antiviral developments against pathogens that until now we’ve had only limited tools to fight.”
A New Approach
RNA viruses thrive by modifying their RNA caps, specialized structures that stabilize viral RNA, enhance its translation, and mimic host mRNA to evade immune defenses. This process relies on enzymes called methyltransferases, making them a tempting target for antiviral therapies. Unlike many existing antivirals that target viral proteases, this new approach focuses on inhibiting methyltransferases.
“Inhibiting methyltransferase required using a non-conventional RNA substrate, adding a new challenge to drug discovery,” Tuschl explained.
Leveraging his expertise in RNA therapeutics, Tuschl restructured his lab during the pandemic to focus on antiviral drug discovery, seeing clear advantages to targeting methyltransferases. His team screened 430,000 compounds and identified a small number of inhibitors for the SARS-CoV-2 methyltransferase NSP14. These compounds were refined through extensive development and testing, showing promising results in cell-based assays and in mice.
The compound demonstrated effectiveness in treating COVID-19, comparable to Paxlovid, and maintained efficacy even when the virus mutated. Tuschl highlighted the potential of combining this new inhibitor with protease inhibitors to prevent viral escape.
Future Implications
The study not only validates viral methyltransferases as promising therapeutic targets but also suggests that this inhibitor would have minimal side effects. Tuschl noted that the compound’s unique mechanism allows it to selectively target the virus without disrupting human processes.
While the compound is not yet ready for human testing, requiring further optimization, the Tuschl lab is expanding its work to explore inhibitors for other viruses, including RSV, dengue, Zika, mpox, and fungal infections, all of which share similar enzymatic vulnerabilities.
“This work opens the door to targeting many pathogens,” Tuschl said. “It’s a new opportunity to prepare for future pandemics.”
For more information, see the original study: Thomas Tuschl, Small-molecule inhibition of SARS-CoV-2 NSP14 RNA cap methyltransferase, Nature (2024). DOI: 10.1038/s41586-024-08320-0.
Journal information: Nature.
