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Tuning the Innate Immune Response to Cyclic Dinucleotides by Using Atomic Mutagenesis |
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| Authors: | Yao Li Dr Andrea Fin Alexander R Rovira Yichi Su Andrew B Dippel Dr Jonathan Andrés Valderrama Dr Angelica M Riestra Prof?Dr Victor Nizet Prof?Dr Ming C Hammond Prof?Dr Yitzhak Tor |
| Affiliation: | 1. Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093-0358 USA;2. Department of Chemistry and Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720 USA;3. Collaborative to Halt Antibiotic-Resistant Microbes, Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093-0760 USA;4. Collaborative to Halt Antibiotic-Resistant Microbes, Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093-0760 USA
Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093-0760 USA;5. Department of Chemistry and Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720 USA Department of Chemistry and Henry Eyring Center for Cell and Genome Sciences, University of Utah, Salt Lake City, UT 84112 USA |
| Abstract: | 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. |
| Keywords: | cyclic dinucleotides innate immune response modified nucleosides STING agonists |