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We now report that GS 4071 is active against several strains of influenza A and B viruses in vitro and that oral GS 4104, an ethyl ester prodrug which is converted to GS 4071 in vivo, is active in the mouse and ferret models of influenza virus infection. Oral administration of 10 mg of GS 4104 per kg of body weight per day caused a 100-fold reduction in lung homogenate viral titers and enhanced survival in mice infected with influenza A or B viruses. In ferrets, a 25-mg\/kg dose of GS 4104 given twice daily reduced peak viral titers in nasal washings and eliminated constitutional responses to influenza virus infection including fever, increased nasal signs (sneezing, nasal discharge, mouth breathing), and decreased activity. Consistent with our demonstration that the parent compound is highly specific for influenza virus neuraminidases, no significant drug-related toxicity was observed after the administration of oral dosages of GS 4104 of up to 800 mg\/kg\/day for 14 days in nonclinical toxicology studies with rats. These results indicate that GS 4104 is a novel, orally active antiviral agent with the potential to be used for the prophylaxis and treatment of influenza A and B virus infections.<\/jats:p>","DOI":"10.1128\/aac.42.3.640","type":"journal-article","created":{"date-parts":[[2018,10,8]],"date-time":"2018-10-08T20:30:35Z","timestamp":1539030635000},"page":"640-646","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":214,"title":["Oral Administration of a Prodrug of the Influenza Virus Neuraminidase Inhibitor GS 4071 Protects Mice and Ferrets against Influenza Infection"],"prefix":"10.1128","volume":"42","author":[{"given":"Dirk B.","family":"Mendel","sequence":"first","affiliation":[{"name":"<!--label omitted: 1-->Gilead Sciences, Inc., Foster City, California 944041;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun Y.","family":"Tai","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Gilead Sciences, Inc., Foster City, California 944041;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul A.","family":"Escarpe","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Gilead Sciences, Inc., Foster City, California 944041;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weixing","family":"Li","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Gilead Sciences, Inc., Foster City, California 944041;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert W.","family":"Sidwell","sequence":"additional","affiliation":[{"name":"<!--label omitted: 2-->Institute for Antiviral Research, Utah State University, Logan, Utah 84322-56002; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John H.","family":"Huffman","sequence":"additional","affiliation":[{"name":"<!--label omitted: 2-->Institute for Antiviral Research, Utah State University, Logan, Utah 84322-56002; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clive","family":"Sweet","sequence":"additional","affiliation":[{"name":"<!--label omitted: 3-->School of Biological Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT,3 and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth J.","family":"Jakeman","sequence":"additional","affiliation":[{"name":"<!--label omitted: 3-->School of Biological Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT,3 and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Merson","sequence":"additional","affiliation":[{"name":"<!--label omitted: 4-->Pfizer Central Research, Sandwich, Kent CT139 NJ,4 United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven A.","family":"Lacy","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Gilead Sciences, Inc., Foster City, California 944041;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Willard","family":"Lew","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Gilead Sciences, Inc., Foster City, California 944041;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew A.","family":"Williams","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Gilead Sciences, Inc., Foster City, California 944041;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijun","family":"Zhang","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Gilead Sciences, Inc., Foster City, California 944041;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming S.","family":"Chen","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Gilead Sciences, Inc., Foster City, California 944041;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norbert","family":"Bischofberger","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Gilead Sciences, Inc., Foster City, California 944041;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Choung U.","family":"Kim","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Gilead Sciences, Inc., Foster City, California 944041;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1992.tb05026.x"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/icb.1948.39"},{"key":"e_1_3_2_4_2","first-page":"165","article-title":"Characterisation of an ionisable group involved in binding and catalysis by sialidase from influenza virus.","volume":"24","author":"Chong A. 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