Scientists blaze new path to fighting viral diseases

(Press-News.org) JUPITER, Fla. — In a quest to develop new antiviral drugs for COVID-19 and other diseases, a collaboration led by scientists at The Wertheim UF Scripps Institute has identified a potential new drug against the virus that causes COVID-19.

In the process, the team devised a powerful new platform for finding medicines to fight many types of infectious diseases.

Writing in the Journal of the American Chemical Society, in an online article posted on Monday, Oct. 6, 2025, the scientists said they began by seeking “druggable pockets” in the stable structures of viral genetic material. Like keyholes, these pockets offer promising spaces to intervene with a precise medication. The team then used systematic chemistry, computational, and robotic drug discovery methods to find and perfect compounds able to function like the keys.

Their refined and optimized compound, dubbed Compound 6, led SARS-CoV-2 viral proteins to misfold, malfunction, and ultimately, be destroyed and removed by cells, in lab tests. Notably, their work could benefit other viral diseases, too, said Matthew D. Disney, Ph.D., Institute Professor and Chair of the chemistry department at The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology.

“The method we have developed can be applied to any number of RNA-based viruses that burden society and have limited treatment options, including influenza, norovirus, MERS, Marburg, Ebola, Zika and more,” Disney said. “We have already started work on several of these.” 

Disney’s collaborators included Arnab Chatterjee, Ph.D., senior vice president of medicinal chemistry at the Skaggs-Calibr Institute for Innovative Medicines, in LaJolla, Calif., and Sumit Chanda, Ph.D., who headed the Center for Antiviral Medicines & Pandemic Preparedness at Scripps Research, part of the National Institutes of Health’s initiative to rebuild the nation’s antiviral medicine cabinet.

“This platform represents a transformative way of thinking about drug discovery,” Chatterjee said. “It has given us a roadmap not only to design antivirals for coronaviruses, but to rapidly extend this strategy to other high-priority RNA targets across infectious disease and beyond.”

The co-first authors were Sandra Kovachka, Ph.D., and Amirhossein Taghavi, Ph.D., of The Wertheim UF Scripps Institute, and Jielei Wang, a graduate student in Disney’s lab.

The SARS-CoV-2 virus is so tiny it would take 1,000 of them lined end-to-end to equal the width of a typical human hair. Still, its string-like genome packs instructions that trick infected cells into making 27 proteins.

One of them, a mechanism called a frameshift element, enables efficient use of the tight viral real estate. The frameshifter looks like a lever and functions much like an engine’s clutch or a 10-speed bike’s derailer. It causes the cell’s protein-building machines to pause while reading the virus’s genome. It then forces the machines to shift their protein-construction starting point, thus directing the cell to assemble a brand new protein for viral replication.

Disney reasoned that this frameshift element, conserved across the many variants of SARS-CoV-2, would serve as an ideal target for an RNA-focused drug.

Until recently, RNA structures have been viewed by scientists as especially challenging drug targets. Disney’s group has long focused on finding RNA structures that are readily druggable, as well as technologies and compound libraries to accomplish that goal, enabling them to make rapid progress.

In the new paper, Disney’s team used both computational and experimental approaches to find the right chemical probes that would allow the team to map the frameshift element’s binding pockets and mutations. Those methods included one Disney invented called Chem-CLIP, or Chemical Cross-Linking and Isolation by Pull-down, helpful for mapping drug-binding pockets.

Further analysis and experimentation revealed that a known compound, mirafloxacin, interfered with assembly of the frameshift element, though not optimally. Robotic high-throughput compound discovery revealed eight related chemical scaffolds that could bind to the mapped structures in a similar fashion. Their antiviral activity was confirmed through experiments on live cells infected with SARS-CoV-2. They found Compound 6 had the optimal impact. Ahead, the team is developing strategies to boost the potency and effectiveness of Compound 6.

Most gratifying about this collaboration, Disney said, is that the team showed how blending expertise and technologies systematically produced a powerful new way to attack viral diseases that have RNA as their genetic basis.

“This strategy offers a directed and unbiased way to rationally design RNA-targeting antiviral small-molecule medications,” said Disney, who directs the institute’s center of excellence, RNA: From Biology to Drug Discovery. “By linking deep structural biology expertise with drug discovery capabilities, we are accelerating the path from basic RNA biology to potential medicines.”

Chanda, whose team conducted the cell-based tests, said this project also demonstrated the rapid, high-impact work accomplished in just the first three years of the NIH’s Antiviral Drug Discovery Centers for Pathogens of Pandemic Concern program, or AViDD for short.

 “This work illustrates exactly what AViDD was designed to do — push forward innovative strategies that expand the antiviral arsenal,” Chanda said. “By showing that RNA can be systematically targeted with drug-like molecules, the team has opened doors for medicines against many viruses, not just SARS-CoV-2.”

 

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