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The 50% effective concentration (EC\n            <jats:sub>50<\/jats:sub>\n            ) for\ninhibition of bovine viral diarrhea virus (BVDV)-induced cytopathic\neffect formation was 0.04 \u00b1 0.01 \u03bcM. Comparable\nreduction of viral RNA synthesis (EC\n            <jats:sub>50<\/jats:sub>\n            = 0.12\u00b1\n0.02 \u03bcM) and production of infectious virus\n(EC\n            <jats:sub>50<\/jats:sub>\n            = 0.074 \u00b1 0.003 \u03bcM) were\nobserved. The selectivity index (ratio of 50% cytostatic\nconcentration\/EC\n            <jats:sub>50<\/jats:sub>\n            ) of BPIP was \u223c2,000. BPIP was\ninactive against the hepatitis C virus subgenomic replicon and yellow\nfever virus but demonstrated weak activity against GB\nvirus. Drug-resistant mutants were at least 300-fold less\nsusceptible to BPIP than wild-type virus; showed cross-resistance to\n            <jats:italic>N<\/jats:italic>\n            -propyl-\n            <jats:italic>N<\/jats:italic>\n            -[2-(2\n            <jats:italic>H<\/jats:italic>\n            -1,2,4-triazino[5,6-b]indol-3-ylthio)ethyl]-1-propanamine\n(VP32947), and carried the F224S mutation in the viral RNA-dependent\nRNA polymerase (RdRp). When the F224S mutation was introduced into an\ninfectious clone, the drug-resistant phenotype was obtained. BPIP did\nnot inhibit the in vitro activity of recombinant BVDV RdRp, but did\ninhibit the activity of replication complexes (RCs). Computational\ndocking revealed that F224 is located at the top of the finger domain\nof the polymerase. Docking of BPIP in the crystal structure of the BVDV\nRdRp revealed aromatic ring stacking, some hydrophobic contacts, and a\nhydrogen bond. Since two structurally unrelated compounds, i.e., BPIP\nand VP32947, target the same region of the BVDV RdRp, this position may\nbe expected to be critical in the functioning of the polymerase or\nassembly of the RC. The potential of BPIP for the treatment of\npestivirus and hepacivirus infections is\ndiscussed.\n          <\/jats:p>","DOI":"10.1128\/jvi.80.1.149-160.2006","type":"journal-article","created":{"date-parts":[[2005,12,13]],"date-time":"2005-12-13T02:52:45Z","timestamp":1134442365000},"page":"149-160","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":71,"title":["A Novel, Highly Selective Inhibitor of Pestivirus Replication That Targets the Viral RNA-Dependent RNA Polymerase"],"prefix":"10.1128","volume":"80","author":[{"given":"Jan","family":"Paeshuyse","sequence":"first","affiliation":[{"name":"Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pieter","family":"Leyssen","sequence":"additional","affiliation":[{"name":"Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"Mabery","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nina","family":"Boddeker","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Vrancken","sequence":"additional","affiliation":[{"name":"Veterinary and Agrochemical Research Centre, Ukkel, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matheus","family":"Froeyen","sequence":"additional","affiliation":[{"name":"Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Israrul H.","family":"Ansari","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Sciences, University of Nebraska\u2014Lincoln, Lincoln, Nebraska"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"He\u0301le\u0300ne","family":"Dutartre","sequence":"additional","affiliation":[{"name":"Laboratory AFMB-UMR 6098, Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jef","family":"Rozenski","sequence":"additional","affiliation":[{"name":"Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura H. V. G.","family":"Gil","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Sciences, University of Nebraska\u2014Lincoln, Lincoln, Nebraska"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carine","family":"Letellier","sequence":"additional","affiliation":[{"name":"Veterinary and Agrochemical Research Centre, Ukkel, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Lanford","sequence":"additional","affiliation":[{"name":"Department of Virology and Immunology, Southwest National Primate Research Center, and Southwest\rFoundation for Biomedical Research, San Antonio, Texas"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bruno","family":"Canard","sequence":"additional","affiliation":[{"name":"Laboratory AFMB-UMR 6098, Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank","family":"Koenen","sequence":"additional","affiliation":[{"name":"Veterinary and Agrochemical Research Centre, Ukkel, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pierre","family":"Kerkhofs","sequence":"additional","affiliation":[{"name":"Veterinary and Agrochemical Research Centre, Ukkel, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruben O.","family":"Donis","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Sciences, University of Nebraska\u2014Lincoln, Lincoln, Nebraska"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Piet","family":"Herdewijn","sequence":"additional","affiliation":[{"name":"Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia","family":"Watson","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erik","family":"De Clercq","sequence":"additional","affiliation":[{"name":"Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerhard","family":"Puerstinger","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Innsbruck, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johan","family":"Neyts","sequence":"additional","affiliation":[{"name":"Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0969-2126(00)80031-3"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.140220397"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-3542(01)00164-4"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.75.8.3527-3536.2001"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.76.7.3482-3492.2002"},{"key":"e_1_3_2_7_2","first-page":"1","volume":"60","year":"2004","unstructured":"Buckwold, V. 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