Repurposing a cancer drug to inhibit enterovirus infection
Mira Laajala
Enteroviruses are highly prevalent viruses that can cause serious acute infections like aseptic meningitis or myocarditis, but most often mild flu-like symptoms in humans. In addition, many studies have suggested that enterovirus infections can contribute to the onset of type 1 diabetes (T1D). Despite of the medical threat and economic costs to healthcare, there are no approved antivirals against enteroviruses and only poliovirus and enterovirus 71 vaccines are available. Repurposing of drugs that are already well characterized, and on the market for other purposes, is one of the more efficient strategies to find antivirals, and put them quicker into practise.
We studied and patented the repurposing of vemurafenib, an FDA-approved RAF kinase inhibitor for treating BRAFV600E mutant-related melanoma, as an antiviral against enteroviruses. We could show that vemurafenib was effective against group A, B, and C enteroviruses, as well as rhinovirus, but not parechovirus or more remote viruses such as Semliki Forest virus, adenovirus, and respiratory syncytial virus. Instead of acting through the RAF/MEK/ERK pathway, vemurafenib inhibited enterovirus translation and replication by affecting the cellular phosphatidylinositol 4-kinase type IIIb (PI4KB), which has earlier been shown to be important in the formation of enteroviral replication organelles during infection. In addition to acute cell models, we showed that vemurafenib could eradicate enterovirus infection in a chronic cell model, as well as in mice. In a follow-up study, we also showed that vemurafenib, and its better tolerated analog PLX7904, attenuated enterovirus infection in clinically relevant cell types related especially to T1D. Our findings open new possibilities for developing drugs against enteroviruses, and evaluating further the potential of vemurafenib as a repurposed drug in clinical care.
