Abstract
ABSTRACTVirus infection of humans and livestock can be devastating for individuals and populations, sometimes resulting in large economic and societal impact. Prevention of virus disease by vaccination or antiviral agents is difficult to achieve. A notable exception was the eradication of human smallpox by vaccination over 30 years ago. Today, humans and animals remain susceptible to poxvirus infections, including zoonotic poxvirus transmission. Here we identified a small molecule, bisbenzimide (bisbenzimidazole), and its derivatives as potent agents against prototypic poxvirus infection in cell culture. We show that bisbenzimide derivatives, which preferentially bind the minor groove of double-stranded DNA, inhibit vaccinia virus infection by blocking viral DNA replication and abrogating postreplicative intermediate and late gene transcription. The bisbenzimide derivatives are potent against vaccinia virus and other poxviruses but ineffective against a range of other DNA and RNA viruses. The bisbenzimide derivatives are the first inhibitors of their class, which appear to directly target the viral genome without affecting cell viability.IMPORTANCE Smallpox was one of the most devastating diseases in human history until it was eradicated by a worldwide vaccination campaign. Due to discontinuation of routine vaccination more than 30 years ago, the majority of today's human population remains susceptible to infection with poxviruses. Here we present a family of bisbenzimide (bisbenzimidazole) derivatives, known as Hoechst nuclear stains, with high potency against poxvirus infection. Results from a variety of assays used to dissect the poxvirus life cycle demonstrate that bisbenzimides inhibit viral gene expression and genome replication. These findings can lead to the development of novel antiviral drugs that target viral genomes and block viral replication.
Highlights
Virus infection of humans and livestock can be devastating for individuals and populations, sometimes resulting in large economic and societal impact
To determine if bisbenzimides have antiviral activity against vaccinia virus (VACV), we tested the abilities of three different bisbenzimides to inhibit viral plaque formation assays: Hoechst 33342 (H4), Hoechst 33258 (H5), and Hoechst 34580 (H8) (Fig. 1A)
Confluent monolayers of African green monkey kidney (BSC40) cells were infected with serial dilutions of the VACV strain Western Reserve (WR), which expresses enhanced green fluorescent protein (EGFP) from an early/late promoter (WR E/L EGFP) in the presence or absence of H4, H5, or H8
Summary
Virus infection of humans and livestock can be devastating for individuals and populations, sometimes resulting in large economic and societal impact. Due to discontinuation of routine vaccination more than 30 years ago, the majority of today’s human population remains susceptible to infection with poxviruses. Underlying technical reasons include diagnosis and viral persistence and the fact that viruses occur in large numbers, are genetically adaptable to environmental pressure, and are highly dependent on their hosts [1,2,3]. This makes it challenging to treat virus infections with compounds that target viral factors such as enzymes or structural proteins. Further agents include the vaccinia virus (VACV) Cantalago virus and cowpox viruses, which are contracted from infected animals and can cause fever and lesions [5,6,7,8,9], and monkeypox, which has a mortality rate estimated around 10% [10] and was responsible for the 2003 poxvirus outbreak in the United States [11, 12]
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