Abstract
There are currently no FDA-approved therapeutics available to treat Rift Valley fever virus (RVFV) infection. In an effort to repurpose drugs for RVFV treatment, a library of FDA-approved drugs was screened to determine their ability to inhibit RVFV. Several drugs from varying compound classes, including inhibitors of growth factor receptors, microtubule assembly/disassembly, and DNA synthesis, were found to reduce RVFV replication. The hepatocellular and renal cell carcinoma drug, sorafenib, was the most effective inhibitor, being non-toxic and demonstrating inhibition of RVFV in a cell-type and virus strain independent manner. Mechanism of action studies indicated that sorafenib targets at least two stages in the virus infectious cycle, RNA synthesis and viral egress. Computational modeling studies also support this conclusion. siRNA knockdown of Raf proteins indicated that non-classical targets of sorafenib are likely important for the replication of RVFV.
Highlights
Rift Valley fever virus (RVFV) is the causative agent of Rift Valley fever, a zoonotic arthropodborne emerging infectious disease endemic to sub-Saharan Africa that has recently spread to parts of the Arabian Peninsula (Ikegami and Makino, 2011)
The condition chosen for the high-throughput assay was multiplicity of infection (MOI) 0.1 since infection at this MOI resulted in the highest Z′ factor (Z′ = 0.89)
These background levels are not related to the infection dynamics, but are experimental artifacts that are primarily the result of (i) virus particles settling on plastic rather than cells that are washed off, (ii) particles that are loosely associated with cell surfaces that become dislodged during washing, and (iii) from Human small airway epithelial cells (HSAECs) that are dislodged during washing. Including this background level of virus has negligible impact on the later time points where the titers are 105 pfu/ml or higher, but in contrast these artifacts can greatly distort data at the early time points where very little de novo synthesized virus is expected to be in the culture supernatant. Because these results suggest the model captured the natural infection dynamics very well, the model was used to begin addressing what step in the virus life cycle could be altered by sorafenib
Summary
Rift Valley fever virus (RVFV) is the causative agent of Rift Valley fever, a zoonotic arthropodborne emerging infectious disease endemic to sub-Saharan Africa that has recently spread to parts of the Arabian Peninsula (Ikegami and Makino, 2011). There is concern that the disease may be able to spread out of endemic areas and further into Asia and Europe or even as far as the western hemisphere (Ikegami, 2012; Rolin et al, 2013). Humans can be exposed to the virus via the inhalational route through contact with infected animal bodily fluids or with contaminated carcasses post-mortem. Aerosol exposure is a route of concern for use of RVFV as a bioweapon (Caroline et al, 2014)
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