Attenuated virulence of pleconaril-resistant coxsackievirus B3 variants.
Pleconaril (VP 63843) is a novel orally bioavailable small molecule with broad antipicornavirus (enterovirus and rhinovirus) activity. Ten independently derived pleconaril-resistant variants of coxsackievirus B3 were isolated from cell culture. The molecular basis of drug resistance and the biologic properties of the drug-resistant viruses were investigated. RNA sequence analysis revealed amino acid changes in the drug-binding pocket of the resistant variants. Thermal stability studies showed the drug-resistant viruses to be significantly less stable than wild type virus. When evaluated in a murine model in which wild type virus infection is 100% lethal, the drug-resistant viruses showed attenuated virulence with both reduced mortality and delayed time to death. Virus titers in heart and spleen were dramatically lower in drug-resistant virus-infected mice than in wild type virus-infected animals. The study results indicate that pleconaril-resistant virus variants are attenuated and significantly less virulent than drug-sensitive wild type virus.
Groarke
J M
JM
ViroPharma Incorporated, Exton, PA 19341, USA. jgroarke@viropharma.com
Pevear
D C
DC
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001665:Binding Sites / Q000235:genetics; D002213:Capsid / Q000235:genetics; D036022:Capsid Proteins; D004352:Drug Resistance, Microbial; D029822:Enterovirus B, Human / Q000187:drug effects* / Q000235:genetics* / Q000472:pathogenicity*; D014644:Genetic Variation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010069:Oxadiazoles / Q000494:pharmacology*; D010080:Oxazoles; D012367:RNA, Viral / Q000235:genetics; D017423:Sequence Analysis, RNA
D000998:Antiviral Agents; D036022:Capsid Proteins; D010069:Oxadiazoles; D010080:Oxazoles; D012367:RNA, Viral; C115201:pleconaril