Identification of novel antipoxviral agents: mitoxantrone inhibits vaccinia virus replication by blocking virion assembly.
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 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 the maximum tolerated dose failed to protect mice against a lethal intranasal infection with vaccinia virus.
Deng
Liang
L
Dermatology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Dai
Peihong
P
Ciro
Anthony
A
Smee
Donald F
DF
Djaballah
Hakim
H
Shuman
Stewart
S
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D024882:Drug Resistance, Viral; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D008942:Mitoxantrone / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D013047:Specific Pathogen-Free Organisms; D014615:Vaccinia / Q000517:prevention & control / Q000821:virology; D014616:Vaccinia virus / Q000187:drug effects* / Q000235:genetics; D014771:Virion / Q000378:metabolism*; D019065:Virus Assembly / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects*
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D008942:Mitoxantrone