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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.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>IMPORTANCE<\/jats:bold>\n                    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.\n                  <\/jats:p>","DOI":"10.1128\/jvi.00838-17","type":"journal-article","created":{"date-parts":[[2017,6,28]],"date-time":"2017-06-28T20:30:22Z","timestamp":1498681822000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":40,"title":["Inhibition of Poxvirus Gene Expression and Genome Replication by Bisbenzimide Derivatives"],"prefix":"10.1128","volume":"91","author":[{"given":"Artur","family":"Yakimovich","sequence":"first","affiliation":[{"name":"Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland"},{"name":"MRC Laboratory for Molecular Cell Biology, University College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moona","family":"Huttunen","sequence":"additional","affiliation":[{"name":"MRC Laboratory for Molecular Cell Biology, University College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benno","family":"Zehnder","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, ETH Zurich, Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lesley J.","family":"Coulter","sequence":"additional","affiliation":[{"name":"Moredun Research Institute, Penicuik, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Gould","sequence":"additional","affiliation":[{"name":"MRC Laboratory for Molecular Cell Biology, University College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Schneider","sequence":"additional","affiliation":[{"name":"Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manfred","family":"Kopf","sequence":"additional","affiliation":[{"name":"Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin J.","family":"McInnes","sequence":"additional","affiliation":[{"name":"Moredun Research Institute, Penicuik, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Urs F.","family":"Greber","sequence":"additional","affiliation":[{"name":"Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Mercer","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, ETH Zurich, Zurich, Switzerland"},{"name":"MRC Laboratory for Molecular Cell Biology, University College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.288.5464.287"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/femsre\/fuw044"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2015.02.039"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1021\/acsinfecdis.7b00009"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2012.11.010"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.3855\/jidc.258"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.3201\/eid1404.070817"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.2340\/00015555-1227"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0055808"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(03)00856-9"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.2007.76.757"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003756"},{"key":"e_1_3_2_14_2","first-page":"84","article-title":"Expected adverse events in a mass smallpox vaccination campaign","volume":"5","author":"Kemper AR","year":"2002","unstructured":"Kemper AR Davis MM Freed GL . 2002. 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