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Antimicrobial Agents and Chemotherapy, February 2007, p. 689-695, Vol. 51, No. 2
0066-4804/07/$08.00+0     doi:10.1128/AAC.00879-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Efficacy of Delayed Treatment with ST-246 Given Orally against Systemic Orthopoxvirus Infections in Mice

University of Alabama School of Medicine, Birmingham, Alabama,¹ Department of Molecular Microbiology and Immunology, Saint Louis University, St. Louis, Missouri,² SIGA Technologies, Inc., Corvallis, Oregon³

Received 17 July 2006/ Returned for modification 28 August 2006/ Accepted 7 November 2006

ST-246 was evaluated for activity against cowpox virus (CV), vaccinia virus (VV), and ectromelia virus (ECTV) and had an in vitro 50% effective concentration (EC₅₀) of 0.48 µM against CV, 0.05 µM against VV, and 0.07 µM against ECTV. The selectivity indices were >208 and >2,000 for CV and VV, respectively. The in vitro antiviral activity of ST-246 was significantly greater than that of cidofovir, which had an EC₅₀ of 41.1 µM against CV and 29.2 µM against VV, with selectivity indices of >7 and >10, respectively. ST-246 administered once daily by oral gavage to mice infected intranasally with CV beginning 4 h or delayed until 72 h postinoculation was highly effective when given for a 14-day duration using 100, 30, or 10 mg/kg of body weight. When 100 mg/kg of ST-246 was administered to VV-infected mice, a duration of 5 days was sufficient to significantly reduce mortality even when treatment was delayed 24 h postinoculation. Viral replication in liver, spleen, and kidney, but not lung, of CV- or VV-infected mice was reduced by ST-246 compared to levels for vehicle-treated mice. When 100 mg/kg of ST-246 was given once daily to mice infected by the intranasal route with ECTV, treatment for 10 days prevented mortality even when treatment was delayed up to 72 h after viral inoculation. Viral replication in target organs of ECTV-infected mice was also reduced.

Published ahead of print on 20 November 2006.

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