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Faced with the resurgence of Oropouche viruses (OROV), Rift Valley fever (RVFV) and Dabie bandavirus (DBV), an American team has just demonstrated that a nucleoside analogue, 4′-fluorouridine (4′-FlU), is capable of stopping these infections, including at an advanced stage, in mice. Published in October 2025 in mBio (American Society for Microbiology),the work carried out by Brian Gowen and Jonna Westover (Utah State University),confirms the potential of this broad-spectrum antiviral,already tested against Sars-CoV-2 or the Lassa virus.
Oropouche, Rift Valley, SFTS: three growing threats
The three pathogens targeted by the study belong to the large bunyavirus family, segmented RNA viruses transmitted by arthropods.
* oropouche virus (OROV), first identified in 1955 in trinidad and Tobago, causes an acute fever that is often mild but sometimes associated with neurological and fetal complications. The ongoing epidemic, which today affects more than 11,000 cases across Latin America but also North America (United States and Canada) and Europe (Germany, Italy, Spain), worries the Pan American health Organization (PAHO) and the WHO.
* The Rift Valley fever virus (RVFV), transmitted by mosquitoes, causes eye infections in humans, sometimes serious and even fatal; it also threatens cattle and sheep herds. Described for the first time in kenya in 1931, it now occurs in the Arabian peninsula and off the coast of East Africa (the Comoros, Mayotte and Madagascar).
* More recent (its first description dates back to 2009 in China), the Dabie bandavirus (DBV) quickly migrated to South and East Asia, particularly to South Korea, Japan, Taiwan, Thailand, Vietnam and Myanmar, where cases of infections have been reported. Particularly feared, this virus causes a syndrome of severe fever with thrombocytopenia (or SFTS), the hospital fatality of which can reach 30%.
No vaccination or specific treatment exists for these infections. Hence the interest in a unique antiviral, administered orally, capable of acting on several of these emerging viruses.
4′-fluorouridine: a strategic nucleoside analogue
4′-Fluorouridine (or EIDD-2749) is an analogue of uridine, one of the four constituents of RNA. By replacing the hydrogen atom of the 4′ carbon with a fluorine atom, the researchers designed a molecule that, once phosphorylated in the cell (as a triphosphate, 4′-FlU-TP), directly interferes with the RNA-dependent RNA polymerase (RdRp) enzyme of RNA viruses. This interaction blocks transcription of the viral genome or causes premature termination of replication, a mechanism already observed for influenza, RSV or SARS-CoV-2.
The target, RdRp, presents high structural conservation between viruses, but has no equivalent in the human cell, which limits toxicity.Furthermore, this enzyme has a strong genetic barrier to resistance, making the rapid emergence of mutants escaping 4′-FlU unlikely.
Impressive results in vitro
the researchers first evaluated the antiviral effectiveness of 4′-FlU in cell cultures infected with the three viruses, comparing it to that of ribavirin and favopiravir. The results are clear:
* Against Oropouche, the 90% effective concentration (EC) is of the order of nanomoles (7.4 nM), i.e.more than 8,000 times more powerful than ribavirin and 2,300 times more than favipiravir.
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Nucleoside Analogues: A Key to Anticipating Future Infectious Crises
Recent outbreaks of mpox, dengue, and Oropouche virus highlight the ongoing threat of emerging infectious diseases. A growing body of research suggests that nucleoside analogues – compounds that resemble the building blocks of RNA and DNA – hold meaningful promise in combating these and future viral threats. New findings demonstrate the effectiveness of 4′-fluorouridine against a range of viruses, underscoring the need for continued investment in this area of research to proactively prepare for the next pandemic.
Understanding Nucleoside Analogues
Nucleoside analogues work by interfering with the replication of viruses. Viruses need to copy their genetic material (RNA or DNA) to spread within a host. These analogues are incorporated into the viral genome during replication, but their altered structure prevents the virus from functioning properly, effectively halting its reproduction. This mechanism makes them broad-spectrum antiviral agents,perhaps effective against a wide range of viruses.
A study published in mBio by Westover et al. (2025) demonstrated the effectiveness of 4′-fluorouridine in treating advanced infections of Oropouche virus, Rift Valley fever virus, and Dabie bandavirus. This research is particularly significant because these viruses represent diverse families and pose distinct challenges to public health. the success of a single compound against all three suggests a potentially worldwide antiviral strategy.
Oropouche Virus
Oropouche virus is a mosquito-borne orthobunyavirus that causes a dengue-like illness. Outbreaks are common in South America, and the virus is expanding its geographic range. The study showed that 4′-fluorouridine significantly reduced viral load and improved outcomes in infected animals.
Rift Valley Fever Virus
Rift Valley fever is a zoonotic virus (transmitted from animals to humans) primarily found in Africa and the Arabian Peninsula. It can cause severe illness in both livestock and humans, leading to significant economic and public health consequences. The research indicated that 4′-fluorouridine effectively controlled the infection in animal models.
Dabie Bandavirus
Dabie bandavirus is a recently discovered virus belonging to the Bandavirus genus. It has been linked to severe fever with thrombocytopenia syndrome (SFTS) in China and other parts of Asia. The study’s findings suggest that 4′-fluorouridine could be a potential therapeutic option for this emerging pathogen.
The Importance of Proactive research
The emergence of mpox, dengue, and Oropouche, alongside the ongoing threat of viruses like Zika and Ebola, underscores the critical need for proactive antiviral research. Waiting for outbreaks to occur before developing treatments is a reactive approach that frequently enough leads to delays and increased morbidity and mortality. Investing in research on broad-spectrum antivirals like nucleoside analogues allows us to anticipate and prepare for future infectious crises.
Key Takeaways
- Nucleoside analogues are promising broad-spectrum antiviral agents.
- 4′-fluorouridine has demonstrated effectiveness against Oropouche virus, Rift Valley fever virus, and Dabie bandavirus in preclinical studies.
- Proactive research on antiviral compounds is crucial for pandemic preparedness.
- Continued investment in this field is essential to protect global public health.
Future Directions
Further research is needed to optimize the use of nucleoside analogues, including determining appropriate dosages, routes of administration, and potential side effects. Clinical trials are essential to evaluate the safety and efficacy of these compounds in humans. Expanding the library of nucleoside analogues and exploring their potential against a wider range of viruses will be critical in building a robust defense against future infectious disease threats.
Reference
- Westover J.B. et al. effective treatment of advanced Oropouche virus, Rift Valley fever virus, and Dabie bandavirus infections with 4′-fluorouridine. mBio, vol. 16, no 10, October 2025. DOI: <
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