Structure‐guided design of immunomodulatory RNA RNA s specifically targeting the cytoplasmic viral RNA RNA sensor RIG RIG ‐I

摘要

The cytoplasmic immune sensor RIG ‐I detects viral RNA and initiates an antiviral immune response upon activation. It has become a potential target for vaccination and immunotherapies. To develop the smallest but potent immunomodulatory RNA (imm RNA s) species, we performed structure‐guided RNA design and used biochemical, structural, and cell‐based methods to select and characterize the imm RNA s. We demonstrated that inserting guanosine at position 9 to the 10mer RNA hairpin (3p10 LG 9) activates RIG ‐I more robustly than the parental RNA . 3p10 LG 9 interacts strongly with the RIG ‐I helicase‐ CTD RNA sensing module and disrupts the auto‐inhibitory interaction between the HEL 2i and CARD s domains. We further showed that 3p10 LA 9 has a stronger cellular activity than 3p10 LG 9. Collectively, purine insertion at position 9 of the imm RNA species triggered more robust activation of RIG ‐1.