title: Design, Synthesis, and Biological Evaluation of Novel Cyclic Adenosine-Inosine Monophosphate (cAIMP) Analogs That Activate Stimulator of Interferon Genes (STING).
abstract: We describe novel STING-activating cyclic dinucleotides whose constituent nucleosides are adenosine and inosine and that vary by ribose substitution, internucleotide linkage position, and phosphate modification. In mammalian cells in vitro, some of these cAIMP analogs induce greater STING-dependent IRF and NF-κB pathway signaling than do the reference agonists for murine (DMXAA) or human (2',3'-cGAMP) STING. In human blood ex vivo, they induce type I interferons (IFNs) and proinflammatory cytokines: for the former, 3',3'-cAIMP (9; EC50of 6.4 μM) and analogs 52-56 (EC50of 0.4-4.7 μM), which contain one or two 2'-fluoro-2'-deoxyriboses and/or bis-phosphorothioate linkages, are more potent than 2',3'-cGAMP (EC50of 19.6 μM). Interestingly, 9 induces type I IFNs more strongly than do its linkage isomers 2',3'-cAIMP (10), 3',2'-cAIMP (23), and 2',2'-cAIMP (27). Lastly, some of the cAIMP analogs are more resistant than 2',3'-cGAMP to enzymatic cleavage in vitro. We hope to exploit our findings to develop STING-targeted immunotherapies.
authors: InvivoGen , 5 Rue Jean Rodier, 31400 Toulouse, France.
authors: Thierry
authors: T
authors: Lioux
authors: InvivoGen , 5 Rue Jean Rodier, 31400 Toulouse, France.
authors: Marc-Antoine
authors: MA
authors: Mauny
authors: InvivoGen , 5 Rue Jean Rodier, 31400 Toulouse, France.
authors: Alain
authors: A
authors: Lamoureux
authors: InvivoGen , 5 Rue Jean Rodier, 31400 Toulouse, France.
authors: Nicolas
authors: N
authors: Bascoul
authors: InvivoGen , 5 Rue Jean Rodier, 31400 Toulouse, France.
authors: Mathieu
authors: M
authors: Hays
authors: InvivoGen , 5 Rue Jean Rodier, 31400 Toulouse, France.
authors: Fabienne
authors: F
authors: Vernejoul
authors: InvivoGen , 5 Rue Jean Rodier, 31400 Toulouse, France.
authors: Anne-Sophie
authors: AS
authors: Baudru
authors: InvivoGen , 5 Rue Jean Rodier, 31400 Toulouse, France.
authors: Cédric
authors: C
authors: Boularan
authors: InvivoGen , 5 Rue Jean Rodier, 31400 Toulouse, France.
authors: Justine
authors: J
authors: Lopes-Vicente
authors: InvivoGen , 5 Rue Jean Rodier, 31400 Toulouse, France.
authors: Gregory
authors: G
authors: Qushair
authors: InvivoGen , 5 Rue Jean Rodier, 31400 Toulouse, France.
authors: Gérard
authors: G
authors: Tiraby
mesh_terms: D000241:Adenosine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D007289:Cyclic IMP / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D051379:Mice; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D016207:Cytokines; D007370:Interferon Type I; D007289:Cyclic IMP; D000241:Adenosine