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RIG-I agonists composed of dsRNA represent antiviral and antitumor therapies, however the development of small-molecule RIG-I agonists, with their potential for improved pharmacokinetics, remains an unmet need. Here, we report small-molecule RIG-I agonists that directly activate the RIG-I receptor protein. These agonists stimulate the first step in RIG-I signaling by triggering release of the signaling domains (CARDs) from an autorepressed form of the protein. This was achieved by developing a sensitive high-throughput screening (HTS) assay that directly monitors CARD expulsion through optical methods. The resulting screen hits were refined and optimized, leading to a specific RIG-I agonist that induces a robust interferon response. This study establishes a pharmacophore and assay for development of small molecules that precisely modulate RIG-I signaling.<\/jats:p>","DOI":"10.1038\/s41467-026-77982-3","type":"journal-article","created":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T09:03:32Z","timestamp":1792400612000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Discovery of direct-acting small-molecule RIG-I agonists through creation of a selective CARD activation platform"],"prefix":"10.1038","volume":"17","author":[{"given":"Rong","family":"Guo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneisha","family":"Norford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9057-0829","authenticated-orcid":false,"given":"Ling","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manyi","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8713-9923","authenticated-orcid":false,"given":"Wenshuai","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2737-9810","authenticated-orcid":false,"given":"Stephanie","family":"Halene","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9045-8872","authenticated-orcid":false,"given":"Anna Marie","family":"Pyle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,19]]},"reference":[{"key":"77982_CR1","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1146\/annurev-med-052814-023338","volume":"67","author":"FJ Barrat","year":"2016","unstructured":"Barrat, F. 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