{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T04:37:01Z","timestamp":1792211821868,"version":"4.4.0"},"reference-count":273,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>Seasonal influenza causes approximately one billion infections and up to 650,000 respiratory deaths annually. Despite decades of antiviral development, the therapeutic arsenal remains constrained by time-dependent efficacy (clinical benefit confined largely to treatment initiated within 48 hours of symptom onset), low genetic resistance barriers (resistance arising from a single point mutation), and critical evidence gaps in high-risk populations. This review critically evaluates the antiviral landscape, focusing on next-generation cap-dependent endonuclease inhibitors (CENIs), resistance implications across all approved drug classes, translational barriers in host-directed therapies and biologics, and H5N1 pandemic preparedness. Suraxavir marboxil, ZX-7101A, and the first approved polymerase basic protein 2 (PB2) inhibitor, onradivir, confirm that scaffold-level optimization (incremental structural refinement within an existing drug class) can meaningfully reduce resistance emergence rates. Across all approved classes, a shared failure pattern is evident: single-target dependence, low-fitness-cost resistance mutations (mutations that confer drug resistance without measurably impairing viral replication or transmission), and a therapeutic window that most patients do not reach. Combination antiviral therapy shows promise for resistance prevention, though the FLAGSTONE Phase 3 trial demonstrated that virological benefit does not consistently translate to clinical outcomes in hospitalized patients. Host-directed therapies and biologics face a shared translational obstacle: the biological window of maximal activity consistently precedes the clinical window of patient presentation, and systemic biologics cannot achieve inhibitory concentrations at the respiratory mucosal surface. For H5N1, preparedness relies on a single observationally supported drug class; baloxavir is absent from most national stockpiles, and no randomized trial data exists for any antiviral in human H5N1 infection. Adaptive trial infrastructure, diversified stockpiling to include next-generation CENIs, and equitable global antiviral access are the most urgent priorities in influenza therapeutics.<\/jats:p>","DOI":"10.3389\/fcimb.2026.1859541","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T04:23:11Z","timestamp":1784866991000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["From neuraminidase inhibitors to novel mechanisms: expanding therapeutic strategies against influenza"],"prefix":"10.3389","volume":"16","author":[{"given":"Yan","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Public Health, International School, Krirk University","place":["Bangkok, Thailand"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Puongtip","family":"Kunanusorn","sequence":"additional","affiliation":[{"name":"Department of Medical and Nursing Science, International College, Krirk University","place":["Bangkok, Thailand"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuang Ming","family":"Tup","sequence":"additional","affiliation":[{"name":"Department of Medical and Nursing Science, International College, Krirk University","place":["Bangkok, Thailand"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santosh","family":"Chokkakula","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Chungbuk National University College of Medicine and Medical Research Institute","place":["Cheongju, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Public Health, International School, Krirk University","place":["Bangkok, Thailand"]},{"name":"Department of Cell Biology, College of Basic Medical Sciences, Tianjin Medical University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1637","DOI":"10.1016\/s0140-6736(21)00676-0","article-title":"Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial","volume":"397","author":"Abani","year":"2021","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3390\/v15010200","article-title":"Broadly protective neuraminidase-based influenza vaccines and monoclonal antibodies: target epitopes and mechanisms of action","volume":"15","author":"Abbadi","year":"2023","journal-title":"Viruses"},{"key":"B3","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1016\/j.cell.2020.04.020","article-title":"Development of CRISPR as an antiviral strategy to combat SARS-CoV-2 and influenza","volume":"181","author":"Abbott","year":"2020","journal-title":"Cell."},{"key":"B4","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1056\/NEJMra0707279","article-title":"Update on avian influenza A (H5N1) virus infection in humans","volume":"358","author":"Abdel-Ghafar","year":"2008","journal-title":"N. 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