Pan-antivirals to combat re-emerging alphaviruses

Mosquito-transmitted alphaviruses are distributed globally and include human pathogens that can cause severe long-term arthritogenic or neurological complications. There are currently no market-approved antivirals or vaccines to treat or prevent these infections. Outbreaks are difficult to predict as they can emerge spontaneously in susceptible human populations. Furthermore, it is challenging to determine the causative pathogen due to great similarities in clinical features of alphavirus-associated diseases. Therefore, drugs with broad-spectrum anti-alphavirus activity could serve as a fast first-line therapy in case of an outbreak. We have performed high-throughput screenings of broad-chemical space libraries and identified a series of small molecules with antiviral activity against different chikungunya virus lineages. Interestingly, we demonstrated that this series exerts broad-spectrum anti-alphavirus activity against a range of arthritogenic alphaviruses. Time-of-addition studies showed that this series has in vitro antiviral activity early in the viral RNA replication stage. Furthermore, these molecules were not cross-resistant with favipiravir-resistant chikungunya virus, a compound that inhibits the viral RNA polymerase. To investigate the mechanism of action in more detail, in vitro resistance selection is currently ongoing. Elucidation of the specific antiviral target of this newly identified series could reveal a new target in the alphavirus proteome, which could be valuable for the development of broad-spectrum anti-alphavirus drugs.