Norovirus replicates in biomolecular condensates

If your holiday season activities include a luxury cruise or feasting on raw oysters, then beware: Norovirus, a gastrointestinal RNA virus that can cause nausea and diarrhea, could be an unwelcome guest at your festivities.

There is currently no good treatment for Norovirus, which is the most common cause of foodborne illness. Thankfully, most people make a full recovery after this seasonal virus runs its course. But now, insights into the underlying biology of Norovirus could pave the way for a future treatment. Research published in Science Advances shows that during Norovirus replication, the virus’ RNA-dependent RNA polymerase (RDRP) protein binds with viral RNA to form biomolecular condensates and a new potential target for antivirals (2024, DOI: 10.1126/sciadv.adp9333).

Biomolecular condensates are droplets in a cell that contain proteins, nucleic acids, and other biological machinery. Molecular processes occur more efficiently within these condensates than if that machinery was simply floating around in solution. Unlike other cellular compartments, condensates form via liquid-liquid phase separation, like droplets of oil in a vinaigrette.

Soni Kaundal, a biochemist at Baylor College of Medicine and lead author on the paper, says that the RDRP protein, which replicates viral RNA, “has a flexible N-terminal arm and can form oligomers in the solution.” Those properties, combined with the ability to bind RNA, make the Norovirus RDRP protein biochemically adept at forming condensates.

These condensates are the “replication factories” for Norovirus, according to B.V. Venkataram Prasad, a structural biologist at Baylor College of Medicine and principal investigator of the research. Other RNA viruses, including SARS-CoV-2, measles, and respiratory syncytial virus (RSV) also replicate in biomolecular condensates, which makes these condensates an intriguing target for the development of new antivirals.

“If you can figure out a small molecule that can actually disrupt the formation or interfere with the formation of these condensates, then you have a drug,” Prasad says. A small molecule with these properties has already been found to be effective at inhibiting replication of RSV.