17-(dimethylaminoethylamino)-17-demethoxygeldanamycin and Foot-and-Mouth-Disease

Productive picornavirus infection requires the hijacking of host cell pathways to aid with the different stages of virus entry, synthesis of the viral polyprotein, and viral genome replication. Many picornaviruses, including foot-and-mouth disease virus (FMDV), assemble capsids via the multimerization of several copies of a single capsid precursor protein into a pentameric subunit which further encapsidates the RNA. Pentamer formation is preceded by co- and posttranslational modification of the capsid precursor (P1-2A) by viral and cellular enzymes and the subsequent rearrangement of P1-2A into a structure amenable to pentamer formation. We have developed a cell-free system to study FMDV pentamer assembly using recombinantly expressed FMDV capsid precursor and 3C protease. Using this assay, we have shown that two structurally different inhibitors of the cellular chaperone heat shock protein 90 (hsp90) impeded FMDV capsid precursor processing and subsequent pentamer formation. Treatment of FMDV permissive cells with the hsp90 inhibitor prior to infection reduced the endpoint titer by more than 10-fold while not affecting the activity of a subgenomic replicon, indicating that translation and replication of viral RNA were unaffected by the drug.

Topics: 3C Viral Proteases; Animals; Benzoquinones; Capsid Proteins; Cell Line; Cell Survival; Cell-Free System; Cricetinae; Cysteine Endopeptidases; Foot-and-Mouth Disease; Foot-and-Mouth Disease Virus; HSP90 Heat-Shock Proteins; Isoxazoles; Lactams, Macrocyclic; Molecular Chaperones; Protein Precursors; Protein Processing, Post-Translational; Resorcinols; RNA, Viral; Viral Proteins; Virus Assembly; Virus Replication