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Currently, there are no approved drugs or vaccines specific to LASV. In this study, high-throughput screening of a fragment-based drug discovery library was performed against LASV entry using a pseudotype virus bearing the LASV envelope glycoprotein complex (GPC). Two compounds, F1920 and F1965, were identified as LASV entry inhibitors that block GPC-mediated membrane fusion. Analysis of adaptive mutants demonstrated that the transient mutants L442F and I445S, as well as the constant mutant F446L, were located on the same side on the transmembrane domain of the subunit GP2 of GPC, and all the mutants conferred resistance to both F1920 and F1965. Furthermore, F1920 antiviral activity extended to other highly pathogenic mammarenaviruses, whereas F1965 was LASV-specific. Our study showed that both F1920 and F1965 provide a potential backbone for the development of lead drugs for preventing LASV infection.<\/jats:p>","DOI":"10.3390\/v14122649","type":"journal-article","created":{"date-parts":[[2022,11,28]],"date-time":"2022-11-28T04:31:16Z","timestamp":1669609876000},"page":"2649","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Screening and Identification of Lassa Virus Entry Inhibitors from a Fragment-Based Drug Discovery Library"],"prefix":"10.3390","volume":"14","author":[{"given":"Yuxia","family":"Hou","sequence":"first","affiliation":[{"name":"State Key Laboratory of Virology, Center for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China"},{"name":"University of the Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Virology, Center for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoying","family":"Jia","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Virology, Center for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China"},{"name":"University of the Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minmin","family":"Zhou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Virology, Center for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China"},{"name":"University of the Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenting","family":"Mao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Virology, Center for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China"},{"name":"University of the Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siqi","family":"Dong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Virology, Center for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China"},{"name":"University of the Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueli","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Virology, Center for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China"},{"name":"State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gengfu","family":"Xiao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Virology, Center for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China"},{"name":"University of the Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8696-9773","authenticated-orcid":false,"given":"Wei","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Virology, Center for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China"},{"name":"University of the Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3023","DOI":"10.1007\/s00705-020-04731-2","article-title":"2020 taxonomic update for phylum Negarnaviricota (Riboviria: Orthornavirae), including the large orders Bunyavirales and Mononegavirales","volume":"165","author":"Kuhn","year":"2020","journal-title":"Arch. 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