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These viruses can cause severe upper respiratory tract infections that contribute to high morbidity and mortality rates. The emergence of drug\u2010resistant influenza viruses has created the need for the development of novel broad\u2010spectrum antivirals. Here, we present a novel anti\u2010influenza agent with new targets and mechanisms of action to address this problem. Our findings led to the discovery of a novel influenza virus inhibitor, a ligustrazine derivative known as <jats:bold>A9<\/jats:bold>. We have found that it exhibits broad\u2010spectrum antiviral properties against influenza A and B viruses (IAV and IBV, respectively), including oseltamivir\u2010resistant strain. Through multiple bioassays such as time\u2010of\u2010addition assay, indirect immunofluorescence assay, and nuclear\u2010cytoplasmic fractionation assay, we demonstrated that <jats:bold>A9<\/jats:bold> inhibits the nuclear export of the viral ribonucleoprotein (vRNP). Furthermore, escape mutant analyses and affinity studies determined by surface plasmon resonance\u00a0indicated that <jats:bold>A9<\/jats:bold> specifically targets the nucleoprotein.\u00a0In addition, four chalcone derivatives developed from <jats:bold>A9<\/jats:bold> (<jats:bold>B14<\/jats:bold>, <jats:bold>B29<\/jats:bold>, <jats:bold>B31<\/jats:bold>, and <jats:bold>B32<\/jats:bold>), were found to effectively inhibit the replication of influenza virus through the same mechanism of action. In this manuscript we highlight <jats:bold>A9<\/jats:bold> and its four derivatives as potential leads for the treatment of IAV and IBV infections, and their unique and novel mechanism of action probable benefit the field of anti\u2010influenza drug discovery.<\/jats:p>","DOI":"10.1002\/jmv.28968","type":"journal-article","created":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T11:14:55Z","timestamp":1690283695000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Discovery of ligustrazine and chalcone derivatives as novel viral nucleoprotein nuclear export inhibitors against influenza viruses"],"prefix":"10.1002","volume":"95","author":[{"given":"Ping","family":"Li","sequence":"first","affiliation":[{"name":"Key Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmaceutical Sciences Shandong University Jinan China"},{"name":"Innovation Research Institute of Traditional Chinese Medicine Shandong University of Traditional Chinese Medicine Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Ju","sequence":"additional","affiliation":[{"name":"Key Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmaceutical Sciences Shandong University Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmaceutical Sciences Shandong University Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6177-0397","authenticated-orcid":false,"given":"Jazmin Galvan","family":"Achi","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, College of Medicine University of Illinois at Chicago Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongwei","family":"Kang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmaceutical Sciences Shandong University Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinmi","family":"Zou","sequence":"additional","affiliation":[{"name":"Key Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry, School of Pharmaceutical Sciences Shandong University Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9172-7824","authenticated-orcid":false,"given":"Ruikun","family":"Du","sequence":"additional","affiliation":[{"name":"Innovation Research Institute of Traditional Chinese Medicine Shandong University of Traditional Chinese Medicine Jinan Shandong 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