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Beyond the poliovirus vaccine, antiviral therapeutics remain unavailable for most picornaviral infections. Moreover, existing inhibitors under development generally exhibit narrow\u2010spectrum activity and low barriers to resistance owing to the high mutability of RNA viral proteins. To address these issues, this study constructed a proteolysis\u2010targeting chimera (PROTAC) targeting the 3C protease (3C\n                    <jats:sup>Pro<\/jats:sup>\n                    ) \u2014 a key viral enzyme essential for picornavirus protein processing, host shutoff, and immune suppression. In enterovirus 71 (EV71), a representative member of the picornavirus family, experimental results showed that PROTAC molecule effectively inhibits viral replication through a dual mechanism of action: directly inhibiting the catalytic function of the 3C\n                    <jats:sup>Pro<\/jats:sup>\n                    and inducing its degradation via the ubiquitin\u2010proteasome pathway. Moreover, this PROTAC molecule not only demonstrated effective degradation of previously reported and AI\u2010predicted potential drug\u2010resistant EV71 mutants, but also exhibited degradation activity against 3C\n                    <jats:sup>Pro<\/jats:sup>\n                    from multiple picornaviruses, indicating its potential for broad\u2010spectrum antiviral activity. By integrating multidisciplinary approaches, this work demonstrates that targeted protein degradation can effectively induce the degradation of 3C\n                    <jats:sup>Pro<\/jats:sup>\n                    in picornaviruses, supporting the development of resistance\u2010resistant, broad\u2010spectrum antiviral agents and highlighting their potential to address evolving viral threats.\n                  <\/jats:p>","DOI":"10.1002\/advs.76662","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T19:52:51Z","timestamp":1784317971000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeted Degradation of Picornaviral 3C Protease via PROTACs Confers High Barrier to Viral Resistance and Broad\u2010Spectrum Antiviral Activity"],"prefix":"10.1002","volume":"13","author":[{"given":"Weilong","family":"Deng","sequence":"first","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology College of Pharmacy KLMDASR of Tianjin and Drug Discovery Center for Infectious Disease Nankai University  Tianjin People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junyu","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology College of Pharmacy KLMDASR of Tianjin and Drug Discovery Center for Infectious Disease Nankai University  Tianjin People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingyue","family":"Pang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology College of Pharmacy KLMDASR of Tianjin and Drug Discovery Center for Infectious Disease Nankai University  Tianjin People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology College of Pharmacy KLMDASR of Tianjin and Drug Discovery Center for Infectious Disease Nankai University  Tianjin People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siqian","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology College of Pharmacy KLMDASR of Tianjin and Drug Discovery Center for Infectious Disease Nankai University  Tianjin People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoliang","family":"You","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology College of Pharmacy KLMDASR of Tianjin and Drug Discovery Center for Infectious Disease Nankai University  Tianjin People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoman","family":"Tian","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology College of Pharmacy KLMDASR of Tianjin and Drug Discovery Center for Infectious Disease Nankai University  Tianjin People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongxin","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology College of Pharmacy KLMDASR of Tianjin and Drug Discovery Center for Infectious Disease Nankai University  Tianjin People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology College of Pharmacy KLMDASR of Tianjin and Drug Discovery Center for Infectious Disease Nankai University  Tianjin People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9916-128X","authenticated-orcid":false,"given":"Luqing","family":"Shang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology College of Pharmacy KLMDASR of Tianjin and Drug Discovery Center for Infectious Disease Nankai University  Tianjin People's Republic of 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