{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T08:04:04Z","timestamp":1771315444153,"version":"3.50.1"},"reference-count":54,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T00:00:00Z","timestamp":1765929600000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Medical Virology"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Interferons constitute the host's primary antiviral defense system. It causes the expression of interferon\u2010stimulated genes (ISGs), including ISG15, which modulate viral replication. Here, we identify the E3 ligase HERC5\u2014a crucial mediator of ISGylation\u2014as an antiviral factor against SARS\u2010CoV\u20102. Analysis using mass spectrometry showed that the viral nucleocapsid (N) protein is directly bound by HERC5, which then catalyzes ISGylation occurs at four lysine residues\u2010K61, K65, K102, and K355\u2010found in the NTD and CTD. Functional assays confirmed that ISGylation at these sites disrupts the N protein's capacity for RNA binding and oligomerization. Conversely, the papain\u2010like protease (PLpro) of SARS\u2010CoV\u20102 cleaves ISG15 conjugates, thereby reversing N protein ISGylation. To discover small molecules that enhance the \u201cHERC5\u2010N\u201d interaction, we developed a NanoLuc luciferase\u2010based screening platform and evaluated 1815 FDA\u2010approved drugs. Albendazole emerged as a potent enhancer of \u201cHERC5\u2010N\u201d binding, further promoted N protein ISGylation, and inhibited viral replication. In vivo, Albendazole treatment reduced viral load and alleviated pulmonary inflammation in a transgenic mouse model of K18\u2010hACE2. Together, these findings reveal the crucial functionality of N protein ISGylation in SARS\u2010CoV\u20102 replication and highlight HERC5\u2010mediated ISGylation as a promising therapeutic target.<\/jats:p>","DOI":"10.1002\/jmv.70751","type":"journal-article","created":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T12:17:58Z","timestamp":1765973878000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Albendazole Suppresses SARS\u2010CoV\u20102 Replication by Enhancing HERC5\u2010Mediated ISGylation of Nucleocapsid Protein"],"prefix":"10.1002","volume":"97","author":[{"given":"Yezi","family":"Wu","sequence":"first","affiliation":[{"name":"Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, The Second Affiliated Hospital, School of Medicine Southern University of Science and Technology Shenzhen Guangdong 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