Tuning the Innate Immune Response to Cyclic Dinucleotides by Using Atomic Mutagenesis.
Yao LiAndrea FinAlexander R RoviraYichi SuAndrew B DippelJonathan Andrés ValderramaAngelica M RiestraVictor NizetMing C HammondYitzhak TorPublished in: Chembiochem : a European journal of chemical biology (2020)
Cyclic dinucleotides (CDNs) trigger the innate immune response in eukaryotic cells through the stimulator of interferon genes (STING) signaling pathway. To decipher this complex cellular process, a better correlation between structure and downstream function is required. Herein, 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. This study demonstrates that CDN analogues bearing modified nucleobases are able to tune the innate immune response in eukaryotic cells.
Keyphrases
- immune response
- biofilm formation
- induced apoptosis
- dendritic cells
- signaling pathway
- cell cycle arrest
- innate immune
- molecular docking
- toll like receptor
- crispr cas
- pseudomonas aeruginosa
- escherichia coli
- pi k akt
- candida albicans
- oxidative stress
- cell death
- genome wide
- molecular dynamics
- structure activity relationship
- dna methylation
- gene expression
- anti inflammatory