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Antimicrobial Agents and Chemotherapy, February 2009, p. 572-579, Vol. 53, No. 2
0066-4804/09/$08.00+0     doi:10.1128/AAC.01257-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Activities of Certain 5-Substituted 4'-Thiopyrimidine Nucleosides against Orthopoxvirus Infections

Earl R. Kern,^1* Mark N. Prichard,¹ Debra C. Quenelle,¹ Kathy A. Keith,¹ Kamal N. Tiwari,² Joseph A. Maddry,² and John A. Secrist III²

Department of Pediatrics, University of Alabama School of Medicine, Birmingham, Alabama,¹ Organic Chemistry Department, Southern Research Institute, Birmingham, Alabama²

Received 19 September 2008/ Returned for modification 22 October 2008/ Accepted 14 November 2008

As part of a program to identify new compounds that have activity against orthopoxviruses, a number of 4'-thionucleosides were synthesized and evaluated for their efficacies against vaccinia and cowpox viruses. Seven compounds that were active at about 1 µM against both viruses in human cells but that did not have significant toxicity were identified. The 5-iodo analog, 1-(2-deoxy-4-thio-β-D-ribofuranosyl)-5-iodouracil (4'-thioIDU), was selected as a representative molecule; and this compound also inhibited viral DNA synthesis at less than 1 µM but only partially inhibited the replication of a recombinant vaccinia virus that lacked a thymidine kinase. This compound retained complete activity against cidofovir- and ST-246-resistant mutants. To determine if this analog had activity in an animal model, mice were infected intranasally with vaccinia or cowpox virus and treatment with 4'-thioIDU was given intraperitoneally or orally twice daily at 50, 15, 5, or 1.5 mg/kg of body weight beginning at 24 to 120 h postinfection and was continued for 5 days. Almost complete protection (87%) was observed when treatment with 1.5 mg/kg was begun at 72 h postinfection, and significant protection (73%) was still obtained when treatment with 5 mg/kg was initiated at 96 h. Virus titers in the liver, spleen, and kidney were reduced by about 4 log₁₀ units and about 2 log₁₀ units in mice infected with vaccinia virus and cowpox virus, respectively. These results indicate that 4'-thioIDU is a potent, nontoxic inhibitor of orthopoxvirus replication in cell culture and experimental animal infections and suggest that it may have potential for use in the treatment of orthopoxvirus infections in animals and humans.

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

Published ahead of print on 24 November 2008.

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Antimicrobial Agents and Chemotherapy, February 2009, p. 572-579, Vol. 53, No. 2
0066-4804/09/$08.00+0     doi:10.1128/AAC.01257-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

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