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Infection may result in mild to severe respiratory disease associated with morbidity and some mortality. Several anti-influenza drugs are available, but these agents target viral components and are susceptible to drug resistance. There is a need for new antiviral drug strategies that include repurposing of clinically approved drugs. Drugs that target cellular machinery necessary for influenza virus replication can provide a means for inhibiting influenza virus replication. We used RNA interference screening to identify key host cell genes required for influenza replication, and then FDA-approved drugs that could be repurposed for targeting host genes. We examined the effects of Clopidogrel and Triamterene to inhibit A\/WSN\/33 (EC<jats:sub>50<\/jats:sub>5.84 uM and 31.48 uM, respectively), A\/CA\/04\/09 (EC<jats:sub>50<\/jats:sub>6.432 uM and 3.32 uM, respectively), and B\/Yamagata\/16\/1988 (EC<jats:sub>50<\/jats:sub>0.28 uM and 0.11 uM, respectively) replication. Clopidogrel and Triamterene provide a druggable approach to influenza treatment across multiple strains and subtypes.<\/jats:p>","DOI":"10.1371\/journal.pone.0259129","type":"journal-article","created":{"date-parts":[[2021,10,29]],"date-time":"2021-10-29T17:25:27Z","timestamp":1635528327000},"page":"e0259129","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Drug repositioning of Clopidogrel or Triamterene to inhibit influenza virus replication in vitro"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4713-2484","authenticated-orcid":true,"given":"Nichole","family":"Orr-Burks","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jackelyn","family":"Murray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle V.","family":"Todd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhijeet","family":"Bakre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2924-9956","authenticated-orcid":true,"given":"Ralph A.","family":"Tripp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,10,29]]},"reference":[{"key":"pone.0259129.ref001","unstructured":"CDC. 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