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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: In an effort to repurpose drugs for RVFV treatment, a library of FDA-approved drugs was screened to determine their ability to inhibit RVFV.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 RVFV replication in multiple cell types. (A) Vero, (B) HSAEC, (C) Huh7 cells infected with rMP12 (MOI 0.1) or (D) Vero cells infected with BSL-3 RVFV strain rZH548 (MOI 0.1) were incubated with either DMSO or sorafenib as described above (Figure 1). Media supernatants were collected 24 hpi and infectious viral titers analyzed by plaque assay. The average and standard deviation of three biological replicates are plotted. *p ≤ 0.01.
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Figure 2: Sorafenib reduces RVFV replication in multiple cell types. (A) Vero, (B) HSAEC, (C) Huh7 cells infected with rMP12 (MOI 0.1) or (D) Vero cells infected with BSL-3 RVFV strain rZH548 (MOI 0.1) were incubated with either DMSO or sorafenib as described above (Figure 1). Media supernatants were collected 24 hpi and infectious viral titers analyzed by plaque assay. The average and standard deviation of three biological replicates are plotted. *p ≤ 0.01.

Mentions: To further validate the ability of sorafenib to inhibit RVFV in a variety of cell backgrounds Vero, HSAEC, or Huh7 cells were examined (Figures 2A–C respectively). Cells infected with rMP12 were pre- and post-treated and infectious titers at 24 hpi were determined by plaque assay. The level of infectious rMP12 virus was significantly reduced by approximately 2–3 logs depending on cell type, confirming that the inhibitory effect of sorafenib was not cell type specific. In addition, BSL-3 RVFV strain ZH548 levels were significantly reduced by close to 4 logs, reaffirming the ability of sorafenib to inhibit RVFV in vitro (Figure 2D).


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 RVFV replication in multiple cell types. (A) Vero, (B) HSAEC, (C) Huh7 cells infected with rMP12 (MOI 0.1) or (D) Vero cells infected with BSL-3 RVFV strain rZH548 (MOI 0.1) were incubated with either DMSO or sorafenib as described above (Figure 1). Media supernatants were collected 24 hpi and infectious viral titers analyzed by plaque assay. The average and standard deviation of three biological replicates are plotted. *p ≤ 0.01.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4495339&req=5

Figure 2: Sorafenib reduces RVFV replication in multiple cell types. (A) Vero, (B) HSAEC, (C) Huh7 cells infected with rMP12 (MOI 0.1) or (D) Vero cells infected with BSL-3 RVFV strain rZH548 (MOI 0.1) were incubated with either DMSO or sorafenib as described above (Figure 1). Media supernatants were collected 24 hpi and infectious viral titers analyzed by plaque assay. The average and standard deviation of three biological replicates are plotted. *p ≤ 0.01.
Mentions: To further validate the ability of sorafenib to inhibit RVFV in a variety of cell backgrounds Vero, HSAEC, or Huh7 cells were examined (Figures 2A–C respectively). Cells infected with rMP12 were pre- and post-treated and infectious titers at 24 hpi were determined by plaque assay. The level of infectious rMP12 virus was significantly reduced by approximately 2–3 logs depending on cell type, confirming that the inhibitory effect of sorafenib was not cell type specific. In addition, BSL-3 RVFV strain ZH548 levels were significantly reduced by close to 4 logs, reaffirming the ability of sorafenib to inhibit RVFV in vitro (Figure 2D).

Bottom Line: In an effort to repurpose drugs for RVFV treatment, a library of FDA-approved drugs was screened to determine their ability to inhibit RVFV.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