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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

Sorafenib reduces viremia while increasing survival in RVFV-infected mice. (A) Uninfected BALB/c mice were treated with 20 mg/kg, 40 mg/kg, or solvent control by oral gavage. Animals were monitored daily for weight loss over 14 days. Percentage of weight maintained (relative to starting weight) was determined. Data plotted represents the mean values and standard deviations of three animals per treatment group. (B) BALB/c mice were infected with 1 × 103 pfu RVFV ZH501 by sub-cutaneous injection. Mice were pretreated 2 h prior to infection, and each day post infection with 30 mg/kg of sorafenib or solvent control via oral gavage. Animals were monitored for 14 days post challenge and survival curves determined. Data plotted represents 10 animals per treatment group. (C) thru (E) Mice infected and treated as described above were sacrificed at 2, 3, and 4 days post infection (dpi). Livers and spleens were harvested. RVFV genomic copies within the spleen (C) or liver (D) were quantified by qRT-PCR for each day. Infectious viral titers (E) were determined for day 4 only by plaque assay. Data plotted represents means and standard deviations from three animals per condition. Filled in circles and open circles represent sorafenib and solvent controls respectively.
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Figure 8: Sorafenib reduces viremia while increasing survival in RVFV-infected mice. (A) Uninfected BALB/c mice were treated with 20 mg/kg, 40 mg/kg, or solvent control by oral gavage. Animals were monitored daily for weight loss over 14 days. Percentage of weight maintained (relative to starting weight) was determined. Data plotted represents the mean values and standard deviations of three animals per treatment group. (B) BALB/c mice were infected with 1 × 103 pfu RVFV ZH501 by sub-cutaneous injection. Mice were pretreated 2 h prior to infection, and each day post infection with 30 mg/kg of sorafenib or solvent control via oral gavage. Animals were monitored for 14 days post challenge and survival curves determined. Data plotted represents 10 animals per treatment group. (C) thru (E) Mice infected and treated as described above were sacrificed at 2, 3, and 4 days post infection (dpi). Livers and spleens were harvested. RVFV genomic copies within the spleen (C) or liver (D) were quantified by qRT-PCR for each day. Infectious viral titers (E) were determined for day 4 only by plaque assay. Data plotted represents means and standard deviations from three animals per condition. Filled in circles and open circles represent sorafenib and solvent controls respectively.

Mentions: Finally experiments were performed to examine whether sorafenib exerted a similar influence on viral replication in vivo as observed in vitro. First, the effect of sorafenib on uninfected BALB/c mice was characterized to determine possible adverse effects by drug treatment. Mice were treated with 20 mg/kg, 40 mg/kg, or solvent control by oral gavage and were monitored daily for weight loss and changes in body condition. The 40 mg/kg dose caused a small decrease in weight between Day 8 and 11 post-treatment, while the 20 mg/kg dose matched the control group weight very closely (Figure 8A). In order to minimize toxicity while still maintaining efficacy of the drug, 30 mg/kg of sorafenib was used to treat mice infected with RVFV ZH501 daily for 10 days. Animals were monitored for 14 days post challenge. Although a trend demonstrating that sorafenib increased survival as compared to control animals was observed, the difference was not statistically significant (Figure 8B). Viral RNA levels in the spleens and livers (Figures 8C,D, respectively) of infected animals were analyzed at 2, 3, and 4 days post-infection (dpi), while day 4 spleen and liver samples were also analyzed for viral titers by plaque assay (Figure 8E). Although not statistically significant, these data demonstrate a trend toward reduction in viral burden at day 4, indicating that sorafenib was effective against RVFV in an in vivo model.


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)

Sorafenib reduces viremia while increasing survival in RVFV-infected mice. (A) Uninfected BALB/c mice were treated with 20 mg/kg, 40 mg/kg, or solvent control by oral gavage. Animals were monitored daily for weight loss over 14 days. Percentage of weight maintained (relative to starting weight) was determined. Data plotted represents the mean values and standard deviations of three animals per treatment group. (B) BALB/c mice were infected with 1 × 103 pfu RVFV ZH501 by sub-cutaneous injection. Mice were pretreated 2 h prior to infection, and each day post infection with 30 mg/kg of sorafenib or solvent control via oral gavage. Animals were monitored for 14 days post challenge and survival curves determined. Data plotted represents 10 animals per treatment group. (C) thru (E) Mice infected and treated as described above were sacrificed at 2, 3, and 4 days post infection (dpi). Livers and spleens were harvested. RVFV genomic copies within the spleen (C) or liver (D) were quantified by qRT-PCR for each day. Infectious viral titers (E) were determined for day 4 only by plaque assay. Data plotted represents means and standard deviations from three animals per condition. Filled in circles and open circles represent sorafenib and solvent controls respectively.
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Figure 8: Sorafenib reduces viremia while increasing survival in RVFV-infected mice. (A) Uninfected BALB/c mice were treated with 20 mg/kg, 40 mg/kg, or solvent control by oral gavage. Animals were monitored daily for weight loss over 14 days. Percentage of weight maintained (relative to starting weight) was determined. Data plotted represents the mean values and standard deviations of three animals per treatment group. (B) BALB/c mice were infected with 1 × 103 pfu RVFV ZH501 by sub-cutaneous injection. Mice were pretreated 2 h prior to infection, and each day post infection with 30 mg/kg of sorafenib or solvent control via oral gavage. Animals were monitored for 14 days post challenge and survival curves determined. Data plotted represents 10 animals per treatment group. (C) thru (E) Mice infected and treated as described above were sacrificed at 2, 3, and 4 days post infection (dpi). Livers and spleens were harvested. RVFV genomic copies within the spleen (C) or liver (D) were quantified by qRT-PCR for each day. Infectious viral titers (E) were determined for day 4 only by plaque assay. Data plotted represents means and standard deviations from three animals per condition. Filled in circles and open circles represent sorafenib and solvent controls respectively.
Mentions: Finally experiments were performed to examine whether sorafenib exerted a similar influence on viral replication in vivo as observed in vitro. First, the effect of sorafenib on uninfected BALB/c mice was characterized to determine possible adverse effects by drug treatment. Mice were treated with 20 mg/kg, 40 mg/kg, or solvent control by oral gavage and were monitored daily for weight loss and changes in body condition. The 40 mg/kg dose caused a small decrease in weight between Day 8 and 11 post-treatment, while the 20 mg/kg dose matched the control group weight very closely (Figure 8A). In order to minimize toxicity while still maintaining efficacy of the drug, 30 mg/kg of sorafenib was used to treat mice infected with RVFV ZH501 daily for 10 days. Animals were monitored for 14 days post challenge. Although a trend demonstrating that sorafenib increased survival as compared to control animals was observed, the difference was not statistically significant (Figure 8B). Viral RNA levels in the spleens and livers (Figures 8C,D, respectively) of infected animals were analyzed at 2, 3, and 4 days post-infection (dpi), while day 4 spleen and liver samples were also analyzed for viral titers by plaque assay (Figure 8E). Although not statistically significant, these data demonstrate a trend toward reduction in viral burden at day 4, indicating that sorafenib was effective against RVFV in an in vivo model.

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