JVI Accepts, published online ahead of print on 10 October 2007
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J. Virol. doi:10.1128/JVI.00770-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Identification of novel antipoxviral agents: Mitoxantrone inhibits vaccinia virus replication by blocking virion assembly

Liang Deng, Peihong Dai, Anthony Ciro, Donald F. Smee, Hakim Djaballah, and Stewart Shuman*

Dermatology Service, Department of Medicine, Molecular Biology Program, and HTS Core Laboratory, Memorial-Sloan-Kettering Cancer Center, New York NY 10021 and Institute for Antiviral Research, Utah State University, Logan UT 84322

* To whom correspondence should be addressed. Email: s-shuman{at}ski.mskcc.org.


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Abstract

The bioterror threat of a smallpox outbreak in an unvaccinated population has mobilized efforts to develop new antipoxviral agents. By screening a library of known drugs, we identified 13 compounds that inhibited vaccinia virus replication at noncytotoxic doses. The anticancer drug mitoxantrone is unique among the inhibitors identified in that it has no apparent impact on viral gene expression. Rather, it blocks processing of viral structural proteins and the assembly of mature progeny virions. The isolation of mitoxantrone-resistant vaccinia strains underscores that a viral protein is the likely target of the drug. Whole-genome sequencing of mitoxantrone-resistant viruses pinpointed missense mutations in the N-terminal domain of vaccinia DNA ligase. Despite its favorable activity in cell culture, mitoxantrone administered intraperitoneally at maximum tolerated dose failed to protect mice against a lethal intranasal infection with vaccinia virus.




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