Tuning the Innate Immune Response to Cyclic Dinucleotides Using Atomic Mutagenesis.

Cyclic dinucleotides (CDNs) trigger the innate immune response in eukaryotic cells through the STING (stimulator of interferon genes) signalling pathway. To decipher this complex cellular process, a better correlation between structure and downstream function is required. Here we report the design and immunostimulatory effect of a novel group of c-di-GMP analogues. By employing an "atomic mutagenesis" strategy, changing one atom at a time, a class of gradually modified CDNs was prepared. These c-di-GMP analogues induce type-I interferon (IFN) production, with some being more potent than c-di-GMP, their native archetype. To the best of our knowledge, this study demonstrates for the first time that CDN analogues bearing modified nucleobases can tune the innate immune response in eukaryotic cells.