Stimulator of interferon genes (STING) agonists are promising candidates for vaccine adjuvants and antitumor immune stimulants. The most potent natural agonist of STING, 2′,3′-cyclic GMP-AMP (2′,3′-cGAMP), is subject to nuclease-mediated inherent metabolic instability, thereby placing limits on its clinical efficacy. Here, we report on a new class of chemically synthesized sugar-modified analogs of 2′,3′-cGAMP containing arabinose and xylose sugar derivatives that bind mouse and human STING alleles with high affinity. The co-crystal structures demonstrate that such analogs act as 2′,3′-cGAMP mimetics that induce the “closed” conformation of human STING. These analogs show significant resistance to hydrolysis mediated by ENPP1 and increased stability in human serum, while retaining similar potency as 2′,3′-cGAMP at inducing IFN-β secretion from human THP1 cells. The arabinose- and xylose-modified 2′,3′-cGAMP analogs open a new strategy for overcoming the inherent nuclease-mediated vulnerability of natural ribose cyclic nucleotides, with the additional benefit of high translational potential as cancer therapeutics and vaccine adjuvants.

干扰素基因刺激剂 （STING） 激动剂是疫苗佐剂和抗肿瘤免疫兴奋剂的有前途的候选药物。最有效的 STING 天然激动剂，2'，3'-环状 GMP-AMP （2'，3'-cGAMP），受核酸酶介导的固有代谢不稳定性的影响，从而限制其临床疗效。在这里，我们报道了一类新的化学合成的 2'，3'-cGAMP 糖修饰类似物，其中包含 阿拉伯糖和木糖衍生物，它们以高亲和力结合小鼠和人 STING 等位基因。共晶体结构表明，此类类似物充当 2'，3'-cGAMP 模拟物，可诱导人类 STING 的“闭合”构象。这些类似物对 ENPP1 介导的水解表现出显著的抗性，并且在人血清中稳定性增加，同时在诱导人 THP1 细胞分泌 IFN β方面保持与 2'，3'-cGAMP 相似的效力。阿拉伯糖和木糖修饰的 2′，3′-cGAMP 类似物为克服天然核糖环核苷酸固有的核酸酶介导的脆弱性开辟了一种新策略，并具有作为癌症治疗剂和疫苗佐剂的高转化潜力的额外优势。