Bis-(3',5')-Cyclic Di-GMP: Promising Adjuvant for Vaccine Design

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

“…3, compound endo-S-cGAMP (6, EC 50 = 27.20 μM) had about twice reduced IRF activity compared to 2′3′cGAMP (EC 50 = 15.47 μM), establishing that the conservative change of 2′3′cGAMP to a 5′-endo-phosphorothioate in 6 leads to a loss in IRF induction in THP1 cells. Interestingly, replacing the 2′OH in compound endo-S-cGAMP (6) to fluorine as in endo-S-cGA F -MP (8) led to 9 times the IRF activity compared to 6 and about 5 times better than 2′3′cGAMP. Also, endo-S-cGA F MP (8) was slightly better than ADU-S100 (4.71 μM).…”

“…3 In addition, purine-based CDNs in bacteria, which contain a canonical 3′-5′ phosphodiester linkage also bind to STING and activates the same downstream signaling as 2′3′cGAMP. [4][5][6][7][8] Type I IFNs are also essential in antitumor immune responses. 9 They activate antigen-presenting dendritic cells (DCs), promote CD8 + T cell proliferation and directly affect cancer cells.…”

“…3 In addition, purine-based CDNs in bacteria, which contain a canonical 3′-5′ phosphodiester linkage also bind to STING and activates the same downstream signaling as 2′3′cGAMP. 4–8…”