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Biotech / Medical : VPHM - Viropharma Inc
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To: scaram(o)uche who wrote ()7/13/1999 10:27:00 AM
From: scaram(o)uche   of 2557
 
J Infect Dis 1999 Jun;179(6):1538-41

Attenuated virulence of pleconaril-resistant coxsackievirus B3 variants.

Groarke JM, Pevear DC

ViroPharma Incorporated, Exton, PA 19341, USA. jgroarke@viropharma.com

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.
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