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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{triangledown}

Debra C. Quenelle,1* R. M. L. Buller,2 Scott Parker,2 Kathy A. Keith,1 Dennis E. Hruby,3 Robert Jordan,3 and Earl R. Kern1

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.

* Corresponding author. Mailing address: The University of Alabama at Birmingham, Department of Pediatrics, 128 Children's Harbor Building, 1600 6th Avenue South, Birmingham, AL 35233-1711. Phone: (205) 934-1990. Fax: (205) 975-1992. E-mail: dquenell{at}uab.edu.

{triangledown} Published ahead of print on 20 November 2006.

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.



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