Bunyaviruses are significant human pathogens, causing diseases MESHD ranging from hemorrhagic fevers MESHD fevers HP to encephalitis MESHD encephalitis HP. Among these viruses, La Crosse virus (LACV), a member of the California serogroup, circulates in the eastern and midwestern United States. While LACV infection is often asymptomatic MESHD asymptomatic TRANS, dozens of cases of encephalitis MESHD encephalitis HP are reported yearly. Unfortunately, no antivirals have been approved to treat LACV infection MESHD. Here, we developed a method to rapidly test SERO potential antivirals against LACV infection MESHD. From this screen, we identified several potential antiviral molecules, including known antivirals. Additionally, we identified many novel antivirals that exhibited antiviral activity without affecting cellular viability. Valinomycin, a potassium ionophore, was among our top targets. We found that valinomycin exhibited potent anti-LACV activity in multiple cell types in a dose-dependent manner. Valinomycin did not affect particle stability or infectivity, suggesting that it may preclude virus replication by altering cellular potassium ions, a known determinant of LACV entry. We extended these results to other ionophores and found that the antiviral activity of valinomycin extended to other viral families including bunyaviruses ( Rift Valley fever MESHD fever HP virus, Keystone virus), enteroviruses (Coxsackievirus, rhinovirus), flavirivuses (Zika), and coronaviruses (229E and MERS-CoV). In all viral infections MESHD, we observed significant reductions in virus titer in valinomycin-treated cells. In sum, we demonstrate the importance of potassium ions to virus infection MESHD, suggesting a potential therapeutic target to disrupt virus replication.
ImportanceNo antivirals are approved for the treatment of bunyavirus infection MESHD. The ability to rapidly screen compounds and identify novel antivirals is one means to accelerate drug discovery for viruses with no approved treatments. We used this approach to screen hundreds of compounds against La Crosse virus, an emerging bunyavirus that causes significant disease MESHD, including encephalitis MESHD encephalitis HP. We identified several known and previously unidentified antivirals. We focused on a potassium ionophore, valinomycin, due to its promising in vitro antiviral activity. We demonstrate that valinomycin, as well as a selection of other ionophores, exhibits activity against La Crosse virus as well as several other distantly related bunyaviruses. We finally observe that valinomycin has activity against a wide array of human viral pathogens, suggesting that disrupting potassium ion homeostasis with valinomycin may be a potent host pathway to target to quell virus infection MESHD.