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Title: Repeated exposure to 5D9, an inhibitor of 3D polymerase, effectively limits the replication of Foot-and-Mouth Disease Virus in host cells.

Author
item RAI, DEVENDRA - Oak Ridge Institute For Science And Education (ORISE)
item Schafer, Elizabeth
item SINGH, KAMALENDRA - University Of Missouri
item MCINTOSH, MARK - University Of Missouri
item SARAFIANOS, STEFAN - University Of Missouri
item Rieder, Aida - Elizabeth

Submitted to: Antiviral Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/28/2013
Publication Date: 4/8/2013
Publication URL: http://handle.nal.usda.gov/10113/56609
Citation: Rai, D.K., Schafer, E.A., Singh, K., Mcintosh, M., Sarafianos, S., Rieder, A.E. 2013. Repeated exposure to 5D9, an inhibitor of 3D polymerase, effectively limits the replication of Foot-and-Mouth Disease Virus in host cells. Antiviral Research. 98(3):380-385 DOI:10.1016/j.antiviral.2013.03.022.

Interpretive Summary: Foot-and-mouth disease virus (FMDV) is the causal agent of an economically devastating disease affecting food animals (e.g. cattle, pigs). Besides the use of vaccines, there is no other therapeutic treatment approved for controlling the disease. Antivirals have been tested in the past with limited success due to the ability of the virus to easily mutate and escape the antiviral inhibition. In this study, we have examined the outcome of long-term exposure to the antiviral compound 5D9 that targets the viral 3D polymerase. This study builds up from the knowledge gained on our previous published work (Durk et al 2010) showing that 5D9 can inhibit FMDV infection in cells. Biological and biochemical assays demonstrated the lack of selection of escape mutants following treatment with 5D9 under the experimental conditions. Further efforts are warranted to test this compound in animals toward the development of an antiviral strategy against FMD.

Technical Abstract: Foot-and-Mouth Disease (FMD) is a highly contagious disease of livestock caused by a highly variable RNA virus that has seven serotypes and more than sixty subtypes. Both prophylactic and post-infection means of controlling the disease outbreak, including universally applicable vaccines and emergency response measures such as therapeutic treatments, are on high demand. In this study, we analyzed the long-term exposure outcome to a previously identified inhibitor of Foot-and-Mouth Disease (FMD) 3Dpolymerase (FMDV 3Dpol) for controlling FMDV infection and for the selection of resistance mutants. The results showed that no escape mutant viruses were isolated from FMDV A24 Cruzeiro infections in cell culture treated with gradually increasing concentrations of the antiviral compound 5D9 over ten generations. Biochemical and plaque assays revealed that the compound, when used at concentrations within a non-toxic range in cells, drove the virus to undetectable levels at passage eight to ten. This is in contrast with observations made on parallel control (untreated) passages exhibiting fully viable and stable virus progenies. Interesting, after repeated simultaneous passages, no resistant mutants were isolated under 5D9 treatment. Collectively, the results demonstrated that under the experimental conditions, treatment with 5D9 does not confer resistance phenotype and over the concentrations used to treat the virus, the virus is unable to abolish the compound-virus interaction. Further efforts using quantitative structure-activity relationship (QSPR) based modifications to make it a more effective inhibitor of 3Dpol may result in the successful development of compound 5D9 as an effective antiviral drug against FMDV.