In an effort to generate novel treatments for COVID‑19 and other viral illnesses, researchers at The Wertheim UF Scripps Institute announced a promising new candidate that targets the virus responsible for the pandemic.
The team also introduced a powerful platform for discovering medicines against a wide variety of infectious diseases.
In a paper published in Journal of the American Chemical Society, the authors explain that they began by searching for “druggable pockets” within the stable structures of viral RNA. These pockets act like keyholes, offering precise entry points for therapeutic molecules. Using a combination of systematic chemistry, computational modeling, and robotic high‑throughput screening, the group found and refined compounds that fit these pockets.
The optimized molecule, designated Compound 6, caused SARS‑CoV‑2 proteins to misfold and malfunction, leading to their degradation by cellular processes in laboratory assays. Importantly, the authors suggest their approach could benefit treatment of other viral diseases as well, according to 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 begun work on several of these.”
Disney’s collaborators include Arnab Chatterjee, Ph.D., senior vice president of medicinal chemistry at the Skaggs‑Calibr Institute for Innovative Medicines in La Jolla, Calif., and Sumit Chanda, Ph.D., who led the Center for Antiviral Medicines & Pandemic Preparedness at Scripps Research, part of the National Institutes of Health’s effort to replenish the nation's antiviral drug library.
“This platform represents a transformative way of thinking about drug discovery,” Chatterjee noted. “It has provided a roadmap not only for designing antivirals against coronaviruses but also for rapidly extending 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 doctoral student in Disney’s laboratory.
The SARS‑CoV‑2 virus is tiny enough that a thousand of them end‑to‑end would match the width of a human hair, yet its linear genome carries instructions for producing 27 viral proteins.
One of these, a frameshift element, functions like a lever that pauses the cell’s protein‑synthesizing machinery, then shifts its reading frame to produce a new protein essential for viral replication.
Disney proposed that this conserved frameshift element could serve as an ideal target for an RNA‑focused drug.
Historically, RNA structures have been considered difficult drug targets. Disney’s group has long aimed to identify druggable RNA foldings and develop the tools to exploit them, which enabled rapid progress in this study.
In the paper, the team combined computational and experimental strategies to locate chemical probes capable of interacting with the frameshift element’s binding pockets and mutations. These approaches included a method invented by Disney, called Chem‑CLIP (chemical cross‑linking and isolation by pull‑down), which facilitates mapping of drug‑binding sites.
Further analysis revealed that the known compound mirafloxacin could interfere with the frameshift element, though it was not optimal. Robotic screening produced eight related chemical scaffolds that bound to the mapped structures in a similar manner. Antiviral activity was validated in live‑cell infections with SARS‑CoV‑2, and Compound 6 emerged as the most effective. The group is now working on strategies to enhance its potency and therapeutic potential.
Disney highlighted that the collaboration demonstrated how systematic integration of diverse expertise and technologies can yield a powerful new approach to tackling RNA‑based viral diseases.
“This strategy offers a directed and unbiased way to rationally design RNA‑targeting antiviral small‑molecule medicines,” Disney said. “By linking deep structural biology with drug discovery capabilities, we are accelerating the journey from basic RNA biology to potential therapies.”
Chanda, who led the cell‑based testing, emphasized that this project exemplifies the rapid, high‑impact work achieved within the first three years of the NIH’s Antiviral Drug Discovery Centers for Pathogens of Pandemic Concern program (AViDD).
“This work demonstrates precisely what AViDD was meant 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.”