Antiviral protects guinea pigs against lethal arenaviruses

Lassa virus is an arenavirus that is endemic to West Africa and is spread by Mastomys rats. In severe cases, the virus can cause hemorrhagic fever. There is no licensed antiviral agent for Lassa virus or for Junin virus, another member of the arenavirus family, which is endemic to Argentina. Researchers have now reported that a compound called 4′-fluorouridine inhibited both Lassa virus and Junin virus in guinea pigs (Sci. Transl. Med. 2024, DOI: 10.1126/scitranslmed.ado7034).

4′-Fluorouridine works against RNA-dependent RNA polymerase, an enzyme that helps viruses assemble RNA. The compound has a similar structure to that of uridine, one of the four ribonucleoside bases that make up RNA, but it has been modified to include a single fluorine atom.

According to George Painter, a biochemist and virologist at Emory University, when the viral polymerase comes across 4′-fluorouridine while trying to elongate RNA, the RNA synthesis process is interrupted.

“It interferes with the mechanism of adding more ribonucleosides and stops it,” says Painter, who led efforts to identify the compound and served as the new study’s principal investigator. “You don’t get full-length genomic RNA, so you don’t get a new virus.”

Previous research has shown that 4′-fluorouridine is effective in small mammals infected with SARS-CoV-2, respiratory syncytial virus, and several influenza viruses. In the new study, scientists observed that the compound was effective against a range of lethal viruses, including arenaviruses, Nipah virus, Crimean-Congo hemorrhagic fever virus, and orthohantaviruses, in cell cultures. RNA-dependent RNA polymerase is highly conserved across RNA viruses, which Painter says makes the enzyme a good target for broad-spectrum antivirals.

Guinea pigs who received 4′-fluorouridine treatment after being infected with either Lassa virus or Junin virus were protected against the virus. Scientists showed that the compound was protective in the animals even when treatment was delayed until after the onset of clinical signs of disease, which Painter says could make the antiviral useful in a real-world scenario. Early Lassa symptoms are hard to differentiate from those of other infections, meaning cases are often diagnosed only when severe symptoms appear later in the disease’s progression.

“I think the authors have really done a nice job showing that this compound is effective against a variety of arenaviruses in cell culture,” says David Safronetz, chief of Special Pathogens at the Public Health Agency of Canada’s National Microbiology Laboratory, who was not involved in the study. “It works in guinea pigs many, many days after infection, and even post onset of clinical disease in these animals. Which is ideal, because that’s the therapeutic window that you’d really be looking for in humans.”