{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T15:07:00Z","timestamp":1789657620716,"version":"4.0.1"},"reference-count":65,"publisher":"Wiley","issue":"47","license":[{"start":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T00:00:00Z","timestamp":1759363200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T00:00:00Z","timestamp":1759363200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Hepatitis E virus (HEV) is the leading cause of acute viral hepatitis worldwide, yet no FDA\u2010approved anti\u2010HEV medication available. Elucidating HEV replication machinery is therefore crucial for identifying novel antiviral targets, and consequently developing potent antivirals. The nonstructural ORF1 polyprotein is pivotal for HEV replication. Herein, it is revealed that the ORF1 X domain is a critical component of HEV replication machinery. Interestingly, the ADP\u2010ribose hydrolase activity of X domain per se is dispensable for HEV replication. Instead, the X domain supports HEV replication through its interdomain interaction with the RNA\u2010dependent RNA polymerase (RdRp). Structure\u2010based functional analysis reveals that X and RdRp jointly create a \u201cpocket\u2010like\u201d cavity (PC) at their interaction interface. Site\u2010directed mutagenesis disrupting the PC integrity completely abolishes HEV replication, demonstrating its crucial role in the viral life cycle. Through a PC\u2010targeted high\u2010throughput in silico screening pipeline, combined with molecular docking analysis, surface plasmon resonance assays, and advanced in vitro HEV models, saikosaponin D and liriopesides B are identified as potent HEV inhibitors targeting this critical interface. Collectively, this study identifies a novel structure within ORF1 polyprotein that is crucial for HEV replication, and demonstrates the feasibility of developing novel antivirals by targeting this PC structure.<\/jats:p>","DOI":"10.1002\/advs.202501699","type":"journal-article","created":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T02:56:42Z","timestamp":1759460202000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Hepatitis E Virus ORF1 Polyprotein Harbors a Pocket\u2010Like Cavity That Is Vital for Virus Replication and Represents a Novel Antiviral Target"],"prefix":"10.1002","volume":"12","author":[{"given":"Xiaohui","family":"Ding","sequence":"first","affiliation":[{"name":"Department of Pathogen Biology and Immunology School of Basic Medical Sciences Xuzhou Medical University Xuzhou 221004 China"},{"name":"Jiangsu Key Laboratory of Immunity and Metabolism Jiangsu International Laboratory of Immunity 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