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Patients infected with ZIKV generally have mild symptoms like a low-grade fever and joint pain. However, severe symptoms can also occur, such as Guillain-Barr\u00e9 syndrome, neuropathy, and myelitis. Pregnant women infected with ZIKV may also cause microcephaly in newborns. To date, we still lack conventional antiviral drugs to treat ZIKV infections. Marine natural products have novel structures and diverse biological activities. They have been discovered to have antibacterial, antiviral, anticancer, and other therapeutic effects. Therefore, marine products are important resources for compounds for innovative medicines. In this study, we identified a marine natural product, harzianopyridone (HAR), that could inhibit ZIKV replication with EC50 values from 0.46 to 2.63 \u00b5M while not showing obvious cytotoxicity in multiple cellular models (CC50 &gt; 45 \u00b5M). Further, it also reduced the expression of viral proteins and protected cells from viral infection. More importantly, we found that HAR directly bound to the ZIKV RNA-dependent RNA polymerase (RdRp) and suppressed its polymerase activity. Collectively, our findings provide HAR as an option for the development of anti-ZIKV drugs.<\/jats:p>","DOI":"10.3390\/molecules29050978","type":"journal-article","created":{"date-parts":[[2024,2,23]],"date-time":"2024-02-23T07:33:56Z","timestamp":1708673636000},"page":"978","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A Marine Natural Product, Harzianopyridone, as an Anti-ZIKV Agent by Targeting RNA-Dependent RNA Polymerase"],"prefix":"10.3390","volume":"29","author":[{"given":"Kexin","family":"Zhang","sequence":"first","affiliation":[{"name":"School of Public Health, Sun Yat-sen University, Guangzhou 510080, China"},{"name":"Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyao","family":"Liang","sequence":"additional","affiliation":[{"name":"School of Public Health, Sun Yat-sen University, Guangzhou 510080, China"},{"name":"Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingzhi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China"},{"name":"School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lishan","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianchen","family":"Yu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China"},{"name":"Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuhan","family":"Xiao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China"},{"name":"Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenjian","family":"He","sequence":"additional","affiliation":[{"name":"School of Public Health, Sun Yat-sen University, Guangzhou 510080, China"},{"name":"Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4799-1345","authenticated-orcid":false,"given":"Huaming","family":"Tao","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4147-5585","authenticated-orcid":false,"given":"Jie","family":"Yuan","sequence":"additional","affiliation":[{"name":"Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China"},{"name":"Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6052","DOI":"10.1016\/j.cell.2021.11.010","article-title":"The epitope arrangement on flavivirus particles contributes to Mab C10\u2019s extraordinary neutralization breadth across Zika and dengue viruses","volume":"184","author":"Sharma","year":"2021","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1128\/CMR.00072-15","article-title":"Zika Virus","volume":"29","author":"Musso","year":"2016","journal-title":"Clin. 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