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Current STING antagonist development has predominantly relied on phenotypic screening strategies. In contrast, we introduce a rational design strategy that directly disrupts STING signaling at its structural origin by covalently targeting cysteine residues within the C\u2010terminal domain (CTD) to prevent functional oligomerization. Through covalent warhead repurposing, we identified P005091, previously known as a USP7 inhibitor, as a STING antagonist that operates via a non\u2010classical nucleophilic displacement mechanism. Mechanistic investigation demonstrated that inhibition by P005091 depends on its concurrent engagement of Cys292 and Cys309, as evidenced by the fact that its activity to block STING oligomerization was abolished only by the C292A\/C309A double mutation. Functionally, P005091 potently suppressed STING signaling and type I interferon responses in vitro and in vivo. Structure\u2010guided optimization yielded the advanced compounds NTP14 and NTP16, which exhibit markedly enhanced cellular potency and robust efficacy in ameliorating type I interferon\u2010driven pathology in multiple preclinical models, including DSS\u2010induced colitis. Our work establishes dual covalent CTD targeting as a transformative strategy for STING antagonist development and opens a new therapeutic avenue for quenching STING\u2010driven inflammation at its source.<\/jats:p>","DOI":"10.1002\/advs.202522764","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T19:14:14Z","timestamp":1774379654000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Dual Covalent Targeting of STING Cysteines 292\/309 Disrupts Functional Oligomerization and Enables Potent Antagonist Development"],"prefix":"10.1002","volume":"13","author":[{"given":"Yuxuan","family":"Zhao","sequence":"first","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment Department of Radiology The First Affiliated Hospital Jinan University  Guangzhou Guangdong China"},{"name":"State Key Laboratory of Anti\u2010Infective Drug Discovery and Development School of Pharmaceutical Sciences Sun Yat\u2010Sen University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Huang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment Department of Radiology The First Affiliated Hospital Jinan University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjing","family":"Qin","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment Department of Radiology The First Affiliated Hospital Jinan University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment Department of Radiology The First Affiliated Hospital Jinan University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology The First Affiliated Hospital Sun Yat\u2010sen University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center For Cancer Sun Yat\u2010sen University Cancer Center  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoquan","family":"Wang","sequence":"additional","affiliation":[{"name":"Laboratory of Chemical Oncogenomics Guangdong Provincial Key Laboratory of Chemical Genomics Peking University Shenzhen Graduate School  Shenzhen Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weilin","family":"Zhou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment Department of Radiology The First Affiliated Hospital Jinan University  Guangzhou Guangdong China"},{"name":"Jiangsu Synthgene Biotechnology Co., Ltd.  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