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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,8,5]]},"abstract":"<jats:p>Influenza represents a significant threat with seasonal epidemics that can transition to global pandemics, and cross-species infection presenting a continuous challenge. While vaccines and several antiviral drugs are available, constant genetic changes vitiate these prevention and treatment options. Consequently, we decided to search for inhibitors against one of the virus\u2019s validated drug targets, its M2 channel that is blocked by aminoadamantanes. Regrettably, widespread mutations in M2 abolish the antiflu activity of said blockers. Therefore, we devised bacteria-based genetic assays that can screen for drugs against aminoadamantane-sensitive and resistant M2 channels and map the resistance potential of any identifiable blocker. Subsequent in cellulo testing and structure\u2013activity relationship studies yielded a synergistic combination of two compounds, Theobromine and Arainosine, that exhibited remarkable antiviral activity by directly inhibiting the virus\u2019s channel. The drug duo was potent against H1N1 pandemic swine flu, H5N1 pandemic avian flu, and aminoadamantane-resistant and sensitive strains alike, exhibiting activity that surpassed oseltamivir, the leading antiflu drug on the market. When this drug duo was tested in an animal model, it once more outperformed oseltamivir, considerably reducing disease symptoms and viral RNA progeny. Importantly, harnessing the bacterial genetic selection, we could demonstrate that the drug duo\u2019s potential for eliciting drug resistance is significantly smaller and molecularly distinct from that of aminoadamantanes. In conclusion, the outcome of this study represents a new potential treatment option for influenza alongside an approach that is sufficiently general and readily applicable to other viral targets.<\/jats:p>","DOI":"10.1073\/pnas.2502240122","type":"journal-article","created":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T17:36:55Z","timestamp":1754069815000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":3,"title":["A bacteria-based search for drugs against avian and swine flu yields a potent and resistance-resilient channel blocker"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5121-2626","authenticated-orcid":false,"given":"Hiya","family":"Lahiri","sequence":"first","affiliation":[{"name":"Department of Biological Chemistry","place":["Jerusalem, Israel"]},{"name":"The Alexander Silberman Institute of Life Sciences","place":["Jerusalem, Israel"]},{"name":"The Hebrew University of Jerusalem","place":["Jerusalem, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eitan","family":"Israeli","sequence":"additional","affiliation":[{"name":"Barry Skolnick Biosafety Level 3 Unit","place":["Jerusalem, Israel"]},{"name":"The Hebrew University of Jerusalem","place":["Jerusalem, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Krugliak","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry","place":["Jerusalem, Israel"]},{"name":"The Alexander Silberman Institute of Life Sciences","place":["Jerusalem, Israel"]},{"name":"The Hebrew University of Jerusalem","place":["Jerusalem, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7513-253X","authenticated-orcid":false,"given":"Kingshuk","family":"Basu","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry","place":["Jerusalem, Israel"]},{"name":"The Alexander Silberman Institute of Life Sciences","place":["Jerusalem, Israel"]},{"name":"The Hebrew University of Jerusalem","place":["Jerusalem, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4655-4645","authenticated-orcid":false,"given":"Yelena","family":"Britan-Rosich","sequence":"additional","affiliation":[{"name":"Barry Skolnick Biosafety Level 3 Unit","place":["Jerusalem, Israel"]},{"name":"The Hebrew University of Jerusalem","place":["Jerusalem, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamar","family":"Ravins Yaish","sequence":"additional","affiliation":[{"name":"Authority For Biological and Biomedical Models","place":["Jerusalem, Israel"]},{"name":"The Hebrew University of Jerusalem","place":["Jerusalem, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7659-1746","authenticated-orcid":false,"given":"Isaiah T.","family":"Arkin","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry","place":["Jerusalem, Israel"]},{"name":"The Alexander Silberman Institute of Life Sciences","place":["Jerusalem, Israel"]},{"name":"The Hebrew University of Jerusalem","place":["Jerusalem, Israel"]},{"name":"Department of Biomedical Engineering","place":["Kowloon, Administrative Regions of China"]},{"name":"College of Biomedicine","place":["Kowloon, Administrative Regions of China"]},{"name":"City University of Hong Kong","place":["Kowloon, Administrative Regions of China"]},{"name":"Hong Kong Special","place":["Kowloon, Administrative Regions of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,8]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.2807\/1560-7917.ES.2024.29.8.2400089"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)33293-2"},{"key":"e_1_3_4_3_2","first-page":"1","article-title":"Mortality in the United States, 2019","volume":"395","author":"Kochanek K. 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