New address: Monoclonal Antibody Discovery (MAD) Lab, Fondazione Toscana Life Sciences, 53100, Siena, Italy.
Department of Chemistry, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377, Munich, Germany.
Angew Chem Int Ed Engl. 2022 Oct 4;61(40):e202207175. doi: 10.1002/anie.202207175. Epub 2022 Aug 31.
2',3'-cGAMP is a cyclic A- and G-containing dinucleotide second messenger, which is formed upon cellular recognition of foreign cytosolic DNA as part of the innate immune response. The molecule binds to the adaptor protein STING, which induces an immune response characterized by the production of type I interferons and cytokines. The development of STING-binding molecules with both agonistic as well as antagonistic properties is currently of tremendous interest to induce or enhance antitumor or antiviral immunity on the one hand, or to treat autoimmune diseases on the other hand. To escape the host innate immune recognition, some viruses encode poxin endonucleases that cleave 2',3'-cGAMP. Here we report that dideoxy-2',3'-cGAMP (1) and analogs thereof, which lack the secondary ribose-OH groups, form a group of poxin-stable STING agonists. Despite their reduced affinity to STING, particularly the compound constructed from two A nucleosides, dideoxy-2',3'-cAAMP (2), features an unusually high antitumor response in mice.
2',3'-cGAMP 是一种环状 A 和 G 核苷酸二核苷酸第二信使，它在细胞识别细胞质外源 DNA 时形成，作为先天免疫反应的一部分。该分子与衔接蛋白 STING 结合，诱导以产生 I 型干扰素和细胞因子为特征的免疫反应。目前，开发具有激动剂和拮抗剂特性的 STING 结合分子，一方面可以诱导或增强抗肿瘤或抗病毒免疫，另一方面可以治疗自身免疫性疾病，这引起了极大的兴趣。为了逃避宿主先天免疫识别，一些病毒编码 poxin 内切酶，切割 2',3'-cGAMP。在这里，我们报告二脱氧-2',3'-cGAMP（1）及其类似物缺乏二级核糖-OH 基团，形成了一组 poxin 稳定的 STING 激动剂。尽管它们与 STING 的亲和力降低，特别是由两个 A 核苷构建的化合物，二脱氧-2',3'-cAAMP（2），在小鼠中具有异常高的抗肿瘤反应。
