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The therapeutic efficacy of current influenza vaccines and small molecule antiviral drugs is limited due to the emergence of multidrug-resistant influenza viruses. In response to the urgent need for the next generation of influenza antivirals, we utilized a fast-track drug discovery platform by exploring multi-component reaction products for antiviral drug candidates. Specifically, molecular docking was applied to screen a small molecule library derived from the Ugi-azide four-component reaction methodology for inhibitors that target the influenza polymerase PA<jats:sub>C<\/jats:sub>-PB1<jats:sub>N<\/jats:sub> interactions. One hit compound <jats:bold>5<\/jats:bold> was confirmed to inhibit PA<jats:sub>C<\/jats:sub>-PB1<jats:sub>N<\/jats:sub> interactions in an ELISA assay and had potent antiviral activity in an antiviral plaque assay. Subsequent structure-activity relationship studies led to the discovery of compound <jats:bold>12a<\/jats:bold>, which had broad-spectrum antiviral activity and a higher <jats:italic>in vitro<\/jats:italic> genetic barrier to drug resistance than oseltamivir. Overall, the discovery of compound <jats:bold>12a<\/jats:bold> as a broad-spectrum influenza antiviral with a high <jats:italic>in vitro<\/jats:italic> genetic barrier to drug resistance is significant, as it offers a second line of defense to combat the next influenza epidemics and pandemics if vaccines and oseltamivir fail to confine the disease outbreak.<\/jats:p>","DOI":"10.1038\/s41598-018-22875-9","type":"journal-article","created":{"date-parts":[[2018,3,9]],"date-time":"2018-03-09T16:08:01Z","timestamp":1520611681000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Exploring Ugi-Azide Four-Component Reaction Products for Broad-Spectrum Influenza Antivirals with a High Genetic Barrier to Drug Resistance"],"prefix":"10.1038","volume":"8","author":[{"given":"Jiantao","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanmei","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher","family":"Foley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuanxiang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rami","family":"Musharrafieh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuting","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yongtao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunlong","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher","family":"Hulme","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4845-4621","authenticated-orcid":false,"given":"Jun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2018,3,15]]},"reference":[{"key":"22875_CR1","unstructured":"Palese, P. & Shaw, M. 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