Discovery of direct-acting small-molecule RIG-I agonists through creation of a selective CARD activation platform.

Small-molecule RIG-I agonists that directly activate the receptor by triggering CARD release were identified and optimized, inducing a robust interferon response.

• Why it matters: RIG-I is crucial for antiviral defense and cancer therapy, but developing small-molecule agonists with better pharmacokinetics remains an unmet challenge, limiting therapeutic options.
• What they did: A high-throughput screening assay was developed to monitor CARD expulsion, leading to the discovery and refinement of specific RIG-I agonists capable of activating RIG-I signaling.
• The result: The identified agonists establish a pharmacophore and assay platform, enabling precise modulation of RIG-I signaling for potential antiviral and antitumor applications.