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Repurposing FDA-approved drugs as therapeutics to treat Rift Valley fever virus infection.

Benedict A, Bansal N, Senina S, Hooper I, Lundberg L, de la Fuente C, Narayanan A, Gutting B, Kehn-Hall K - Front Microbiol (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University Manassas, VA, USA.

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.

No MeSH data available.


Related in: MedlinePlus

Comparison between experimental data and the computational model for HSAEC infection. (A) Virus in the culture supernatant (2–24 hpi) after the addition of sorafenib (gray bars) or DMSO-vehicle (black bars). Data are average pfu/ml ± standard deviations and each bar represents three biological replicates. (B) Schematic of the computational model showing uninfected HSAECs (U), early infected HSAECs (E), infected virus-producing HSAECs (I) and Virus particles (V) (see text for additional details). (C) Comparison between experimental data and model results. Open circles are the DMSO-vehicle data reproduced from (A) and the dashed line is pfu/ml data produced from the computational model using the parameter values summarized in Table 1.
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Figure 6: Comparison between experimental data and the computational model for HSAEC infection. (A) Virus in the culture supernatant (2–24 hpi) after the addition of sorafenib (gray bars) or DMSO-vehicle (black bars). Data are average pfu/ml ± standard deviations and each bar represents three biological replicates. (B) Schematic of the computational model showing uninfected HSAECs (U), early infected HSAECs (E), infected virus-producing HSAECs (I) and Virus particles (V) (see text for additional details). (C) Comparison between experimental data and model results. Open circles are the DMSO-vehicle data reproduced from (A) and the dashed line is pfu/ml data produced from the computational model using the parameter values summarized in Table 1.

Mentions: To provide data for a computational model, the growth of RVFV MP12 in vitro with and without sorafenib treatment was characterized (summarized in Figure 6A). HSAECs were pre-treated with either DMSO or sorafenib and then infected with RVFV at an MOI of 0.1. After 1 h incubation, the inoculum was removed and the wells were washed with PBS to remove free virus (inoculum and washes are referred to as unabsorbed virus in Figure 6A). Thereafter, the respective drug media (or vehicle control) was put back onto the wells and culture supernatants were collected and viral titers were determined by plaque assay. As shown, sorafenib prevented an increase in viral titers over the entire experimental time course.


Repurposing FDA-approved drugs as therapeutics to treat Rift Valley fever virus infection.

Benedict A, Bansal N, Senina S, Hooper I, Lundberg L, de la Fuente C, Narayanan A, Gutting B, Kehn-Hall K - Front Microbiol (2015)

Comparison between experimental data and the computational model for HSAEC infection. (A) Virus in the culture supernatant (2–24 hpi) after the addition of sorafenib (gray bars) or DMSO-vehicle (black bars). Data are average pfu/ml ± standard deviations and each bar represents three biological replicates. (B) Schematic of the computational model showing uninfected HSAECs (U), early infected HSAECs (E), infected virus-producing HSAECs (I) and Virus particles (V) (see text for additional details). (C) Comparison between experimental data and model results. Open circles are the DMSO-vehicle data reproduced from (A) and the dashed line is pfu/ml data produced from the computational model using the parameter values summarized in Table 1.
© Copyright Policy
Related In: Results  -  Collection

License
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Figure 6: Comparison between experimental data and the computational model for HSAEC infection. (A) Virus in the culture supernatant (2–24 hpi) after the addition of sorafenib (gray bars) or DMSO-vehicle (black bars). Data are average pfu/ml ± standard deviations and each bar represents three biological replicates. (B) Schematic of the computational model showing uninfected HSAECs (U), early infected HSAECs (E), infected virus-producing HSAECs (I) and Virus particles (V) (see text for additional details). (C) Comparison between experimental data and model results. Open circles are the DMSO-vehicle data reproduced from (A) and the dashed line is pfu/ml data produced from the computational model using the parameter values summarized in Table 1.
Mentions: To provide data for a computational model, the growth of RVFV MP12 in vitro with and without sorafenib treatment was characterized (summarized in Figure 6A). HSAECs were pre-treated with either DMSO or sorafenib and then infected with RVFV at an MOI of 0.1. After 1 h incubation, the inoculum was removed and the wells were washed with PBS to remove free virus (inoculum and washes are referred to as unabsorbed virus in Figure 6A). Thereafter, the respective drug media (or vehicle control) was put back onto the wells and culture supernatants were collected and viral titers were determined by plaque assay. As shown, sorafenib prevented an increase in viral titers over the entire experimental time course.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University Manassas, VA, USA.

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.

No MeSH data available.


Related in: MedlinePlus