title: Repeated exposure to 5D9, an inhibitor of 3D polymerase, effectively limits the replication of foot-and-mouth disease virus in host cells.
abstract: Foot-and-mouth disease (FMD) is a highly contagious disease of livestock caused by a highly variable RNA virus (FMDV) 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 3D polymerase (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 (4-chloro-N'-thieno, [2,3-d]pyrimidin-4-ylbenzenesulfonohydrazide) over ten passages. Biochemical and plaque assays revealed that when 5D9 was used at concentrations within a non-toxic range in cells, it 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. Collectively, the results demonstrated that under the experimental conditions, treatment with 5D9 does not confer a resistant phenotype and the virus is unable to evade the antiviral effect of the inhibitor. Further efforts using quantitative structure-property relationship (QSPR) based modifications of the 5D9 compound may result in the successful development of an effective in vivo antiviral drug targeting FMDV.
authors.affiliation: Foreign Animal Disease Research Unit, United States Department of Agriculture, Agricultural Research Service, Plum Island Animal Disease Center, Greenport, NY 11944-0848, USA.
authors.forename: Devendra K
authors.initials: DK
authors.lastname: Rai
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Schafer
authors.forename: Kamalendra
authors.initials: K
authors.lastname: Singh
authors.forename: Mark A
authors.initials: MA
authors.lastname: McIntosh
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Sarafianos
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Rieder
mesh_terms: D000818:Animals; D000956:Antigens, Viral; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D024882:Drug Resistance, Viral; D029544:Foot-and-Mouth Disease Virus / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D050296:Microbial Viability / Q000187:drug effects; D012254:Ribavirin / Q000494:pharmacology; D012692:Serial Passage; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000187:drug effects*
chemical_list: C585141:4-chloro-N'-thieno(2,3-d)pyrimidin-4-ylbenzenesulfonohydrazide; D000956:Antigens, Viral; D000998:Antiviral Agents; D006574:Heterocyclic Compounds, 2-Ring; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C103557:virus-infection-associated antigen, Foot-and-mouth disease virus; D012254:Ribavirin