{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T16:38:03Z","timestamp":1772728683196,"version":"3.50.1"},"reference-count":71,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T00:00:00Z","timestamp":1759276800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Flaviviruses, such as dengue, Zika, and Langat virus (LGTV), pose significant global health threats, highlighting the urgent need for broad-spectrum antiviral therapies. This study focuses on the NS3 helicase of LGTV, a key enzyme in viral replication, aiming to elucidate its structure and identify high-potency inhibitors to facilitate rational drug design.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The study employed an integrated approach: 1) Structural Biology: Determining the crystal structure of apo LGTV helicase. 2) Comparative Analysis: Aligning the structure with Zika (ZIKV) and dengue (DENV) virus helicases to assess conformational flexibility. 3) Virtual Screening: Screening 11,027 compounds to identify high-affinity inhibitors. 4) Molecular Modeling: Validating binding modes and stability via molecular docking and dynamics simulations. 5) Experimental Validation: Assessing pan-flavivirus affinity of lead compounds using Isothermal Titration Calorimetry (ITC).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results and discussion<\/jats:title><jats:p>The cloverleaf-shaped architecture of LGTV helicase was resolved, revealing conserved ATP- and RNA-binding sites. LGTV exhibited an intermediate conformational flexibility upon ATP binding compared to ZIKV and DENV helicases. Virtual screening identified six high-affinity hits, notably the repurposed drug Zafirlukast. Zafirlukast demonstrated a dual-targeting mechanism, engaging both the ATPase pocket and RNA-binding cleft. Molecular dynamics confirmed stable binding, and ITC validated its broad-spectrum affinity across flaviviruses. The study establishes the LGTV helicase as a robust model for antiviral development. Zafirlukast emerges as a promising prototype for dual-target inhibitors, capable of simultaneously obstructing ATP hydrolysis and RNA unwinding. These findings provide a strong foundation for designing novel broad-spectrum therapeutics against neurotropic flaviviruses.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcimb.2025.1664344","type":"journal-article","created":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T05:51:57Z","timestamp":1759297917000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Structural elucidation of Langat virus helicase unveils dual-target inhibition for broad-spectrum anti-flaviviruses strategy"],"prefix":"10.3389","volume":"15","author":[{"given":"Ruixue","family":"Li","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhen","family":"Han","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rongrong","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chen","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1080\/14787210.2019.1635009","article-title":"Broad-spectrum antiviral agents: A crucial pandemic tool","volume":"17","author":"Adalja","year":"2019","journal-title":"Expert Rev. anti-infective Ther."},{"key":"B2","doi-asserted-by":"publisher","first-page":"105074","DOI":"10.1016\/j.antiviral.2021.105074","article-title":"Targeting the NS2B-NS3 protease of tick-borne encephalitis virus with pan-flaviviral protease inhibitors","volume":"190","author":"Akaberi","year":"2021","journal-title":"Antiviral Res."},{"key":"B3","doi-asserted-by":"publisher","first-page":"500","DOI":"10.4269\/ajtmh.1976.25.500","article-title":"Isolation of Langat virus from Haemaphysalis papuana Thorell in Thailand","volume":"25","author":"Bancroft","year":"1976","journal-title":"Am. 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