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

Guang Yang,⁵ Daniel C. Pevear,^1, Marc H. Davies,^1, Marc S. Collett,^1, Tom Bailey,^1,¶ Susan Rippen,^1,|| Linda Barone,^1,# Chris Burns,^1, Gerry Rhodes,¹ Sanjeev Tohan,^1, John W. Huggins,³ Robert O. Baker,^3, R. L. Mark Buller,² Erin Touchette,² Kem Waller,² Jill Schriewer,² Johan Neyts,⁴ Erik DeClercq,⁴ Kevin Jones,⁵ Dennis Hruby,⁵ and Robert Jordan^5*

ViroPharma, Inc., Exton, Pennsylvania,¹ Saint Louis University, St. Louis, Missouri,² United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland,³ Rega Institute for Medical Research KULeuven, Leuven, Belgium,⁴ SIGA Technologies, Inc., Corvallis, Oregon⁵

Received 12 May 2005/ Accepted 14 July 2005

ST-246 is a low-molecular-weight compound (molecular weight = 376), that is potent (concentration that inhibited virus replication by 50% = 0.010 µM), selective (concentration of compound that inhibited cell viability by 50% = >40 µM), 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 (LD₅₀) 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 LD₅₀) of vaccinia virus. Orally administered ST-246 also protected A/NCr mice from lethal infection, following intranasal inoculation with 40,000x LD₅₀ of ectromelia virus. Infectious virus titers at day 8 postinfection in liver, spleen, and lung from ST-246-treated animals were below the limits of detection (<10 PFU/ml). In contrast, mean virus titers in liver, spleen, and lung tissues from placebo-treated mice were 6.2 x 10⁷, 5.2 x 10⁷, and 1.8 x 10⁵ PFU/ml, respectively. Finally, oral administration of ST-246 inhibited vaccinia virus-induced tail lesions in Naval Medical Research Institute mice inoculated via the tail vein. Taken together, these results validate F13L as an antiviral target and demonstrate that an inhibitor of extracellular virus formation can protect mice from orthopoxvirus-induced disease.

Present address: Progenics Pharmaceuticals, Inc., Tarrytown, NY.

Present address: Bristol Myers Squibb Company, Princeton, NJ.

Present address: ViroDefense, Inc., Washington, DC.

^¶ Present address: Cephalon, Inc., West Chester, PA.

^|| Present address: Gentera, Inc., Malvern, PA.

^# Present address: AstraZeneca, Wilmington, DE.

Present address: Protez, Inc., Malvern, PA.

Present address: Exelixis, Inc., San Francisco, CA.

Present address: American Type Culture Collection, Manassas, VA.

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