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Previously, we identified the enteroviral 3A protein as a viral suppressor of RNAi (VSR) that functions through homodimerization to inhibit the antiviral RNA interference (RNAi) pathway. Herein, capitalizing on this homodimerization mechanism, we rationally designed 3A\u2010targeting broad\u2010spectrum anti\u2010enteroviral molecular glues targeting the dimeric interface to induce dysfunctional dimerization. The optimal compound, VTP\u201032, exhibited good binding affinity with 3A (K\n                    <jats:italic>\n                      <jats:sub>D<\/jats:sub>\n                    <\/jats:italic>\n                    = 0.29\u00a0\u00b5\n                    <jats:sc>m<\/jats:sc>\n                    ), potent and pan\u2010enterovirus (groups A, B, D) antiviral effects (EC\n                    <jats:sub>50<\/jats:sub>\n                    = 0.21\u20130.92\u00a0\u00b5\n                    <jats:sc>m<\/jats:sc>\n                    ), and good safety (CC\n                    <jats:sub>50<\/jats:sub>\n                    &gt; 500\u00a0\u00b5\n                    <jats:sc>m<\/jats:sc>\n                    ). VTP\u201032 treatment (20\u00a0mg\/kg) could effectively reduce viral load, alleviate clinical symptoms, and improve survival in EV\u2010A71\u2010infected mouse models. Mechanistic studies revealed that VTP\u201032 stabilizes 3A protein into an abnormal dimer, promotes viral siRNA generation, and ultimately leads to RNAi\u2010mediated viral genome degradation. Overall, this study provides a promising countermeasure against enteroviral diseases and a rational design strategy for developing antiviral molecular glues.\n                  <\/jats:p>","DOI":"10.1002\/advs.75317","type":"journal-article","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T19:32:35Z","timestamp":1776367955000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Rational Design of Broad\u2010Spectrum Anti\u2010Enteroviral Molecular Glues Targeting Enteroviral RNAi Suppressors"],"prefix":"10.1002","volume":"13","author":[{"given":"Yuan","family":"Fang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Virology and Biosafety Wuhan Institute of Virology Chinese Academy of Sciences  Wuhan Hubei China"},{"name":"University of Chinese Academy of Sciences  Beijing 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