A High-Throughput Screen to Identify Small Molecular Inhibiting Yellow Fever Virus Infection

Abstract

Yellow Fever (YF) caused by yellow fever virus (YFV) has historically been a threat to global health. This risk posed by YFV was highly mitigated with the development of the vaccine strain YFV-17D, but challenges caused by this virus linger despite global vaccination attempts. With outbreaks occurring in urban areas in the past 20 years and the lack of an antiviral for YFV, there is demand for expanding the arsenal of global health tools to fight against Flaviviruses like YFV.

To address this gap, a high-throughput screen was done on the ~75,000 molecules in the Princeton University Small Molecule Library to find a compound that exhibited antiviral activity against YFV while also maintaining low cytotoxicity. The initial screen identified 626 molecules with antiviral activity, of which 43 were determined to be noncytotoxic. While these initial stages of the screen seemed promising, we were unable to identify a molecule that consistently exhibited antiviral activity. Of the 43 molecules that continued to the second round of screening, 5 exhibited a titratable effect where an increase in concentration led to a decrease in viral activity. Those 5 were preliminarily retested but did not validate the original antiviral activity exhibited in the initial screening process.

Due to time constraints, more thorough workup could not be completed to establish firmly whether any of the compounds are suitable for further refinement in structure activity relationship analysis. It is also conceivable that some of these compounds may exhibit antiviral activity against other related flaviviruses. Moreover, the search for an antiviral that acts on YFV can continue by screening other molecule libraries or identifying targets in the YFV replication cycle.