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The highly conserved viral 3C protease has been the primary target for antiviral development, but competitive inhibitors targeting its active site does not meet expectations in clinical studies. Previously, an unconventional allosteric site is identified on human rhinovirus 14 (HRV14) 3C, representing novel opportunities for pan\u2010enterovirus antivirals development. Here, in silico screening of 143,621 natural products against this allosteric site is performed and 28 candidate molecules are identified, among which dihydromyricetin (DHM) and oridonin\u2010A1 bind to HRV14 3C and allosterically inhibit its protease activity. Moreover, DHM shows minimal cytotoxicity and potent antiviral efficacy against HRV14 infections across different cell models, with selective indexes exceeding 700. Structural analysis and mutagenesis assays further pinpoint key 3C residues essential for DHM binding. Consistent with the high conservation of these residues across\n                    <jats:italic>Enterovirus<\/jats:italic>\n                    genus, DHM broadly binds and efficiently inhibits 3C proteases from not only rhinoviruses, but also coxsackieviruses, enteroviruses and polioviruses. These findings establish DHM as a unique, broad\u2010spectrum allosteric inhibitor of\n                    <jats:italic>Enterovirus<\/jats:italic>\n                    3C proteases and underscore its potential as a promising candidate for the development of pan\u2010enterovirus antivirals.\n                  <\/jats:p>","DOI":"10.1002\/adbi.202400845","type":"journal-article","created":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T09:32:57Z","timestamp":1752139977000},"source":"Crossref","is-referenced-by-count":1,"title":["A Pan\u2010Enterovirus Natural Product Inhibitor Targeting a Unique Allosteric Site on the Viral 3C Protease"],"prefix":"10.1002","volume":"9","author":[{"given":"Shangwu","family":"Sun","sequence":"first","affiliation":[{"name":"Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech University  Shanghai 201210 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