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One peptide-conjugated PMO (PPMO) binds to the 5\u2032 terminus of the viral genome (5\u2032-end PPMO); the other targets an essential 3\u2032 RNA element required for genome cyclization (3\u2032 conserved sequence I [3\u2032 CSI] PPMO). The 3\u2032 CSI PPMO displayed a broad spectrum of antiflavivirus activity, suppressing WNV, Japanese encephalitis virus, and St. Louis encephalitis virus, as demonstrated by reductions in viral titers of 3 to 5 logs in cell cultures, likely due to the absolute conservation of the 3\u2032 CSI PPMO-targeted sequences among these viruses. The selection and sequencing of PPMO-resistant WNV showed that the 5\u2032-end-PPMO-resistant viruses contained two to three mismatches within the PPMO-binding site whereas the 3\u2032 CSI PPMO-resistant viruses accumulated mutations outside the PPMO-targeted region. The mutagenesis of a WNV infectious clone demonstrated that the mismatches within the PPMO-binding site were responsible for the 5\u2032-end PPMO resistance. In contrast, a U insertion or a G deletion located within the 3\u2032-terminal stem-loop of the viral genome was the determinant of the 3\u2032 CSI PPMO resistance. In a mouse model, both the 5\u2032-end and 3\u2032 CSI PPMOs (administered at 100 or 200 \u03bcg\/day) partially protected mice from WNV disease, with minimal to no PPMO-mediated toxicity. A higher treatment dose (300 \u03bcg\/day) caused toxicity. Unconjugated PMOs (3 mg\/day) showed neither efficacy nor toxicity, suggesting the importance of the peptide conjugate for efficacy. The results suggest that a modification of the peptide conjugate composition to reduce its toxicity yet maintain its ability to effectively deliver PMO into cells may improve PMO-mediated therapy.<\/jats:p>","DOI":"10.1128\/aac.00069-07","type":"journal-article","created":{"date-parts":[[2007,5,8]],"date-time":"2007-05-08T00:33:55Z","timestamp":1178584435000},"page":"2470-2482","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":88,"title":["In Vitro Resistance Selection and In Vivo Efficacy of Morpholino Oligomers against West Nile Virus"],"prefix":"10.1128","volume":"51","author":[{"given":"Tia S.","family":"Deas","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, School of Public Health, State University of New York, Albany, New York 12201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corey J.","family":"Bennett","sequence":"additional","affiliation":[{"name":"Wadsworth Center, New York State Department of Health"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan A.","family":"Jones","sequence":"additional","affiliation":[{"name":"Wadsworth Center, New York State Department of Health"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Tilgner","sequence":"additional","affiliation":[{"name":"Wadsworth Center, New York State Department of Health"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Ren","sequence":"additional","affiliation":[{"name":"Wadsworth Center, New York State Department of Health"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa J.","family":"Behr","sequence":"additional","affiliation":[{"name":"Wadsworth Center, New York State Department of Health"},{"name":"Department of Biomedical Sciences, School of Public Health, State University of New York, Albany, New York 12201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Stein","sequence":"additional","affiliation":[{"name":"AVI BioPharma Inc., Corvallis, Oregon 97333"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick L.","family":"Iversen","sequence":"additional","affiliation":[{"name":"AVI BioPharma Inc., Corvallis, Oregon 97333"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura D.","family":"Kramer","sequence":"additional","affiliation":[{"name":"Wadsworth Center, New York State Department of Health"},{"name":"Department of Biomedical Sciences, School of Public Health, State University of New York, Albany, New York 12201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen A.","family":"Bernard","sequence":"additional","affiliation":[{"name":"Wadsworth Center, New York State Department of Health"},{"name":"Department of Biomedical Sciences, School of Public Health, State University of New York, Albany, New York 12201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei-Yong","family":"Shi","sequence":"additional","affiliation":[{"name":"Wadsworth Center, New York State Department of Health"},{"name":"Department of Biomedical Sciences, School of Public Health, State University of New York, Albany, New York 12201"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2761.2005.00641.x"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.79.11.6631-6643.2005"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.71.9.6433-6444.1997"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1099\/vir.0.18860-0"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/0042-6822(88)90468-0"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/0042-6822(86)90012-7"},{"key":"e_1_3_2_8_2","first-page":"1043","year":"2001","unstructured":"Burke, D. 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