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With deaths from the 1918 influenza pandemic estimated at &gt;50,000,000 and future pandemics anticipated, the need for a potent influenza treatment is critical. In this study, we design and synthesize a bifunctional small molecule by conjugating the neuraminidase inhibitor, zanamivir, with the highly immunogenic hapten, dinitrophenyl (DNP), which specifically targets the surface of free virus and viral-infected cells. We show that this leads to simultaneous inhibition of virus release, and immune-mediated elimination of both free virus and virus-infected cells. Intranasal or intraperitoneal administration of a single dose of drug to mice infected with 100x MLD\n                    <jats:sub>50<\/jats:sub>\n                    virus is shown to eradicate advanced infections from representative strains of both influenza A and B viruses. Since treatments of severe infections remain effective up to three days post lethal inoculation, our approach may successfully treat infections refractory to current therapies.\n                  <\/jats:p>","DOI":"10.1038\/s41467-020-19386-5","type":"journal-article","created":{"date-parts":[[2020,11,5]],"date-time":"2020-11-05T06:03:19Z","timestamp":1604556199000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["A universal dual mechanism immunotherapy for the treatment of influenza virus infections"],"prefix":"10.1038","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2173-4201","authenticated-orcid":false,"given":"Xin","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boning","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingcai","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanan S.","family":"Haymour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7376-6029","authenticated-orcid":false,"given":"Fenghua","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Le-cun","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3056-4571","authenticated-orcid":false,"given":"Madduri","family":"Srinivasarao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9042-5528","authenticated-orcid":false,"given":"Philip S.","family":"Low","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,11,5]]},"reference":[{"key":"19386_CR1","unstructured":"Centers for Disease Control and Prevention (CDC), Estimated Range of Annual Burden of Flu in the U.S. since 2010; www.cdc.gov\/flu\/about\/burden."},{"key":"19386_CR2","unstructured":"Centers for Disease Control and Prevention (CDC), Influenza (Flu) in the Workplace; www.cdc.gov\/niosh\/topics\/flu\/activities."},{"key":"19386_CR3","doi-asserted-by":"publisher","first-page":"354","DOI":"10.1111\/irv.12383","volume":"10","author":"JP Weir","year":"2016","unstructured":"Weir, J. 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