Fluorinated cGAMP analogs, which act as STING agonists and are not cleavable by poxins: Structural basis of their function.

The cGAS-STING pathway is a crucial part of innate immunity; it serves to detect DNA in the cytoplasm and to defend against certain cancers, viruses, and bacteria. We designed and synthesized fluorinated carbocyclic cGAMP analogs, MD1203 and MD1202D (MDs), to enhance their stability and their affinity for STING. These compounds demonstrated exceptional activity against STING. Despite their distinct chemical modifications relative to the canonical cyclic dinucleotides (CDNs), crystallographic analysis revealed a binding mode with STING that was consistent with the canonical CDNs. Importantly, MDs were resistant to cleavage by viral poxin nucleases and MDs-bound poxin adopted an unliganded-like conformation. Moreover, MDs complexed with poxin showed a conformation distinct from cGAMP bound to poxin, closely resembling their conformation when bound to STING. In conclusion, the development of MD1203 and MD1202D showcases their potential as potent STING activators with remarkable stability against poxin-mediated degradation—a crucial characteristic for future development of antivirals. [Display omitted] • MD1203 and MD1202D described as high-affinity STING agonists • MDs resist cleavage by viral nuclease poxin • MDs' poxin binding differs from cGAMP yet is similar to cGAMP:STING binding mode • MDs exhibit potential for antiviral development by offering enhanced stability Klima, Dejmek, Duchoslav et al. discover MD1203 and MD1202D, which are fluorinated cGAMP analogs targeting the STING pathway with enhanced potency and exhibit improved stability against viral nucleases. [ABSTRACT FROM AUTHOR]