Novel ionophores active against La Crosse virus identified through rapid antiviral screening

Zachary J. Sandler; Michelle N. Vu; Vineet D. Menachery; Bryan C. Mounce

daptomycin, among others. More closely related to LACV, a RVFV screen highlighted azauridine 86 and mitoxatrone 16 . The ability to rapidly screen molecules highlights an opportunity to identify both 87 unique virus-specific and broad-spectrum antivirals, as these reports have highlighted. 88 4 viral processes has several benefits, including potential for broad-spectrum activity and a 92 heightened requirement for antiviral resistance beyond minor mutations in the virus. Additionally, 93 numerous approved and available drugs are already available that can be repurposed as 94 antivirals 18, 19 . While significant work remains to be done to identify and verify such antivirals, 95 rapidly screening compounds can provide insight. 96 97 Using the NIH's Developmental Therapeutics Program (DTP), we obtained and screened >500 98 compounds for activity against LACV. We identified several known antivirals, including 99 deoxyuridine and quinonone. Importantly, we also identified a variety of novel classes of antivirals, 100 including metal ion chelators. Valinomycin, a top hit in our screen, functions by transporting 101 potassium ions against the electrochemical gradient. We investigated the antiviral activity of 102 valinomycin, observing that valinomycin exhibits antiviral activity in several cellular systems, in a 103 dose-dependent manner and independent of treatment time. We also found that valinomycin does 104 not directly inactivate viral particles, highlighting a cellular role for potassium ions in virus infection. 105