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Climate change and the expanding geographical distribution of mosquito vectors transmitting orthoflaviviruses have increased their potential to cause large-scale disease outbreaks. The frequency and severity of disease outbreaks highlight the urgent need for a broad-spectrum antiviral agent targeting orthoflaviviruses. In this work, we conducted a comprehensive morphological profiling of approximately 200,000 small molecules through a fluorescence-based high-content imaging platform, which led to the identification of a singular small molecule exhibiting broad-spectrum activity against orthoflaviviruses. Subsequent hit deconvolution against DENV serotype 2 (DENV-2) revealed NS2A protein as a novel therapeutic target. Mechanistically, JNJ-1953 inhibits viral RNA synthesis, as demonstrated by robust reductions in intracellular viral RNA and infectious virus production. Additional experiments show that JNJ-1953 further impacts viral RNA packaging and interferes with the interaction between NS2A and prM, rendering the molecule a multimodal inhibitor.<\/jats:p>","DOI":"10.1371\/journal.ppat.1014190","type":"journal-article","created":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T17:37:47Z","timestamp":1778002667000},"page":"e1014190","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["An orthoflavivirus inhibitor targeting multifunctional NS2A protein, a previously unidentified target"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1803-7509","authenticated-orcid":true,"given":"Doortje","family":"Borrenberghs","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kitti Wing Ki","family":"Chan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sven","family":"Van Brandt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steffen","family":"Jaensch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Milly Ming Ju","family":"Choy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peggy","family":"Geluykens","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Asmae El","family":"Bouayadi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dax","family":"Lauwers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pradeep","family":"Bist","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bart","family":"Stoops","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeroen","family":"Van de Ven","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Vermeulen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah","family":"Megens","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kim","family":"Thys","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dani\u00eblle","family":"Peeters","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suzanne J. 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