The cGAS-STING pathway plays a vital role in innate immunity by detecting cytoplasmic DNA and providing defense against specific cancers, viruses, and bacteria. In this study, we synthesized fluorinated carbocyclic cGAMP analogs, MD1203 and MD1202D (referred to as MDs), with the aim of improving their stability and enhancing their affinity for STING. Our findings demonstrate that these compounds exhibit significant activity against STING. Despite their unique chemical modifications compared to the conventional cyclic dinucleotides (CDNs), analysis through crystallography revealed a binding mode with STING consistent with that of CDNs. Notably, MDs showed resistance to cleavage by viral poxin nucleases, and the poxin bound to MDs adopted an unliganded-like conformation. Furthermore, the complex formed between MDs and poxin exhibited a distinct conformation from that of cGAMP bound to poxin, closely resembling their conformation when bound to STING. In summary, the development of MD1203 and MD1202D highlights their potential as potent activators of STING, possessing remarkable stability against degradation by poxin—a crucial characteristic for the future development of antiviral agents.
This research was funded by the project the National Institute Virology and Bacteriology (Programme EXCELES, Project No. LX22NPO5103) - Funded by the European Union - Next Generation EU