Design, Synthesis, and Biological Evaluation of Novel Cyclic Adenosine-Inosine Monophosphate (cAIMP) Analogs That Activate Stimulator of Interferon Genes (STING)
Design, Synthesis, and Biological Evaluation of Novel Cyclic Adenosine-Inosine Monophosphate (cAIMP) Analogs That Activate Stimulator of Interferon Genes (STING)
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DOI：
10.1021/acs.jmedchem.6b01300
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发表时间：
2016-11-24
影响因子：
7.3
通讯作者：
Tiraby, Gerard
中科院分区：
文献类型：
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作者：
Lioux, Thierry;Mauny, Marc-Antoine;Tiraby, Gerard
我们新型的 STING 激活环状二核苷酸，其组成核苷是腺苷和肌苷，并且因核糖取代、核苷酸间连接位置和磷酸修饰而异。在体外的哺乳动物细胞中，与鼠 (DMXAA) 或人 (2',3'-cGAMP) STING 的参考激动剂相比，其中一些 cAIMP 类似物诱导更强的 STING 依赖性 IRF 和 NF-kappa B 通路信号传导。在离体人体血液中，它们诱导 I 型干扰素 (IFN) 和促炎细胞因子：对于前者，3',3'-cAIMP（9；EC50 为 6.4 μM）和类似物 52-56（EC50 为 0.4-4.7 μM）含有一个或两个 2'-氟-2'-脱氧核糖和/或二硫代磷酸酯键，比前者更有效。 2',3'-cGAMP（EC50 为 19.6 μM）。有趣的是，9 比其连接异构体 2',3'-cAIMP (10)、3',2'-cAIMP (23) 和 2',2'-cAIMP (27) 更强烈地诱导 I 型 IFN。最后，一些 cAIMP 类似物比 2',3'-cGAMP 更能抵抗体外酶促裂解。我们希望利用我们的发现来开发针对 STING 的免疫疗法。
We 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-kappa B 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; EC50 of 6.4 mu M) and analogs 52-56 (EC50 of 0.4-4.7 mu M), which contain one or two 2'-fluoro-2'-deoxyriboses and/or bis-phosphorothioate linkages, are more potent than 2',3'-cGAMP (EC50 of 19.6 mu M). 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.