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The budding of many enveloped RNA viruses is facilitated by the hijacking of the host endosomal sorting complex required for transport (ESCRT) proteins through viral late domains. These late domains are essential for progeny virus production and are highly conserved, making the interaction between late domains and host ESCRT proteins a potential target for the development of antiviral therapeutics. In this study, we elucidated the functional role of the conserved YRTL motif within the glycoprotein Gn cytoplasmic tail of <jats:italic>Orthohantavirus hantanense<\/jats:italic> (Hantaan virus, HTNV), demonstrating that HTNV production is regulated by the interaction between YRTL and the ESCRT accessory protein ALIX (ALG\u20102 interacting protein X). Through virtual molecule docking screening, followed by in vitro and in vivo assays, we discovered a novel compound, AN\u2010329, which disrupts the YRTL\u2212ALIX interaction and effectively inhibits infectious HTNV production, as well as Crimean\u2212Congo hemorrhagic fever virus (CCHFV) and Rift Valley fever virus (RVFV) VLP release. This makes AN\u2010329 a promising therapeutic candidate for reducing viral dissemination. Given that YRTL is conserved across many hantaviruses, our findings may serve as a prototype for the development of broad\u2010spectrum antiviral drugs.<\/jats:p>","DOI":"10.1002\/jmv.70182","type":"journal-article","created":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T13:56:26Z","timestamp":1737986186000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["A Novel HTNV Budding Inhibitor Interferes the Interaction Between Viral Glycoprotein and Host ESCRT Accessory Protein ALIX"],"prefix":"10.1002","volume":"97","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-4966-7129","authenticated-orcid":false,"given":"Qikang","family":"Ying","sequence":"first","affiliation":[{"name":"Department of Microbiology, School of Basic Medicine Air Force Military Medical University Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxiao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Microbiology, School of Basic Medicine Air Force Military Medical University Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengzheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry and Pharmaceutical Analysis, School of Pharmacy Air Force Military Medical University Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianle","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Pathogen Biology, College of Basic Medical Science Chongqing Medical University Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junmei","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Life Sciences Yan'an University Yan'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjie","family":"Feng","sequence":"additional","affiliation":[{"name":"College of Life Sciences Yan'an University Yan'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongjing","family":"Li","sequence":"additional","affiliation":[{"name":"College of Life Sciences Yan'an University Yan'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhang","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Microbiology, School of Basic Medicine Air Force Military Medical University Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingan","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Microbiology, School of Basic Medicine Air Force Military Medical University Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Microbiology, School of Basic Medicine Air Force Military Medical University Xi'an China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,1,27]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2009040"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00705-019-04253-6"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.3855\/jidc.317"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/1469-0691.12291"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.3947\/ic.2021.0148"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/v11070610"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2015.01326"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/v13081561"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/v6041801"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/bs.aivir.2017.02.002"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.08.023"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.8.3195"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1159\/000331995"},{"issue":"2","key":"e_1_2_10_15_1","first-page":"149","article-title":"Interruption Study of Viremia of Patients With Hemorrhagic Fever With Renal Syndrome in the Febrile Phase","volume":"104","author":"Yang Z. 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