Efficacy and cytotoxicity of novel antiviral compounds against Rift Valley Fever Virus

Rift Valley Fever virus (RVFV) is a ss-RNA virus from the Bunyaviridae family found in Africa and the Arabian Peninsula. The virus is usually transmitted by mosquitoes and predominantly affects livestock; however, humans exposed to bodily fluids or tissue from infected animals can also be infected. In humans, Rift Valley Fever is usually characterized by mild febrile illness; however, in rare cases, the disease becomes more severe and can cause liver disease, encephalitis, vision loss, and hemorrhagic fever. Epizootic RVF can lead to abortion storms in which nearly 100% of pregnancies in infected ruminants result in abortion. RVFV is considered a bioterrorism threat and outbreaks have significant socio-economic impacts. Currently, there are no approved vaccines or therapeutics against RVFV for use in humans. Identification of a safe and effective therapeutic is crucial to public health’s success in the prevention, treatment, and control of Rift Valley Fever. Antiviral properties of compound A3 were identified from a high-throughput screening assay with influenza-A virus. While the mechanism of action of M4 is unknown, A3 is thought to target the enzyme Dihydroorotate Dehydrogenase (DHODH) involved in the de novo pyrimidine biosynthesis pathway. Compound A3 has broad-spectrum antiviral activity and was shown to be effective against both DNA and RNA viruses including, VSV, HCV and HIV-1. To determine efficacy against RVFV, Vero E6 cells were incubated with compounds A3, M4, and Favipiravir (T-705), a known inhibitor of RVFV, at various concentrations with the MP-12 vaccine strain. Viral titer reduction was measured using plaque assay. CC50 and inhibitory concentrations were estimated using non-linear regression and selectivity indexes were calculated. Compound A3 was highly effective with an IC50 of 48nM and low cytotoxicity with a CC50 of 453μM, for a SI of ~9,450 compared to a SI of ~1,550 for T-705. Due to high cytotoxicity, M4 had a relatively low selectivity index. However, comparison between CC50 and selectivity indexes of A3 with that of M4 and T-705 is limited due to differences in duration of compound exposure. Nevertheless, compound A3 was effective in inhibiting viral replication at very low concentrations and shows promise as a potential candidate for antiviral therapy against Rift Valley Fever