Pattern recognition receptors (PRRs) recognize not only pathogens but also self-molecules known as danger associated molecular patterns (DAMPs). The recognition of DAMPs results in the activation of inflammatory responses that lead to the exacerbation of inflammatory and autoimmune diseases. Among the DAMPs, nucleic acids are one of the most efficient endogenous PRR ligands that induce type I IFN. As the blockade of PRR responses to nucleic acids can inhibit inflammatory and autoimmune diseases in mice models, various type of PRR targeting agents have been developed. On the other hand, however, it is also known that there are a variety of nucleic acid sensors that recognize a variety of nucleic acids released from dead cells. It is worth noting that one nucleic acid can be recognized by several sensors, and in some cases, one PRR activate both stimulatory and inhibitory responses. These facts indicate that the simple inhibition of single PRR is not efficient for the therapy. Considering these circumstances, the inhibition of specific immunogenic nucleic acid but not its sensor can be more effective for the therapy; however, there is no effective drug targeting the endogenous immunogenic nucleic acids.
We isolated nucleic acid targeting low molecular compound KN69 (tentative name) that strongly inhibits ssRNA sensing TLR responses. We found that KN69 has strong therapeutic effect on mice inflammatory disease model related to endogenous RNA, indicating that KN69 targets the unknown endogenous immunogenic nucleic acids in vivo. We further tried to isolate endogenous target of KN69 and found that one of them showed strong activity to activate inflammatory cytokine gene induction. I will show more recent progress about this study in my presentation.