An Orally Bioavailable Antipoxvirus Compound (ST-246) Inhibits Extracellular Virus Formation and Protects Mice from Lethal Orthopoxvirus Challenge

作者：Guang Yang, Daniel C. Pevear, Marc H. Davies, Marc S. Collett, Tom Bailey, Susan Rippen, Linda R. Barone, C. R. Burns, Gerry Rhodes, Sanjeev Tohan, John W. Huggins, Robert O. Baker, R. L. Mark Buller, Erin Touchette, Kem Waller, Jill Schriewer, Johan Neyts, Erik De Clercq, Kevin F. Jones, Dennis E. Hruby, Robert Jordan · 发表于：Journal of Virology · 年份：2005 · DOI：10.1128/jvi.79.20.13139-13149.2005 · 被引用次数：460 · 研究领域：Poxvirus research and outbreaks、Herpesvirus Infections and Treatments、Bacillus and Francisella bacterial research

ST-246 is a low-molecular-weight compound (molecular weight = 376), that is potent (concentration that inhibited virus replication by 50% = 0.010 microM), selective (concentration of compound that inhibited cell viability by 50% = >40 microM), and active against multiple orthopoxviruses, including vaccinia, monkeypox, camelpox, cowpox, ectromelia (mousepox), and variola viruses. Cowpox virus variants selected in cell culture for resistance to ST-246 were found to have a single amino acid change in the V061 gene. Reengineering this change back into the wild-type cowpox virus genome conferred resistance to ST-246, suggesting that V061 is the target of ST-246 antiviral activity. The cowpox virus V061 gene is homologous to vaccinia virus F13L, which encodes a major envelope protein (p37) required for production of extracellular virus. In cell culture, ST-246 inhibited plaque formation and virus-induced cytopathic effects. In single-cycle growth assays, ST-246 reduced extracellular virus formation by 10 fold relative to untreated controls, while having little effect on the production of intracellular virus. In vivo oral administration of ST-246 protected BALB/c mice from lethal infection, following intranasal inoculation with 10x 50% lethal dose (LD(50)) of vaccinia virus strain IHD-J. ST-246-treated mice that survived infection acquired protective immunity and were resistant to subsequent challenge with a lethal dose (10x LD(50)) of vaccinia virus. Orally administered ST-246 also...