PDE-stable 2′3′-cGAMP analogues, containing 5′-S-phosphorothioester linkage, as STING agonists

5'-S-phosphorothioester linkage) would not have chirality at phosphorus and hence not pose diastereomer separation problems. Herein, we report the design and synthesis of novel 5'-endo-phosphorothioate substituted 2'3'cGAMP analogues that are hydrolytically stable towards both ectonucleotide phosphodiesterase I (ENPP1, a mammalian phosphodiesterase) and poxvirus immune nucleases (poxin, a phosphodiesterase in Poxvirus) but retains STING-TBK1-IRF activation, comparable to clinical candidate, ADU-S100 in THP1 monocytes.