Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Laboratory of RNA Molecular Biology, The Rockefeller University, New York, NY 10065, USA.
Cell Chem Biol. 2023 Nov 16;30(11):1366-1376.e7. doi: 10.1016/j.chembiol.2023.07.002. Epub 2023 Aug 2.
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.
干扰素基因刺激物（STING）激动剂是疫苗佐剂和抗肿瘤免疫刺激剂的有前途的候选物。STING 的最有效天然激动剂 2'，3'-环鸟苷酸-AMP（2'，3'-cGAMP）易受核酸酶介导的固有代谢不稳定性的影响，从而限制了其临床疗效。在这里，我们报告了一类新的化学合成的糖修饰的 2'，3'-cGAMP 类似物，包含阿拉伯糖和木糖糖衍生物，它们与人和小鼠的 STING 等位基因具有高亲和力。共晶结构表明，这些类似物作为 2'，3'-cGAMP 的模拟物，诱导人 STING 的“封闭”构象。这些类似物对 ENPP1 介导的水解具有显著的抗性，并在人血清中增加了稳定性，同时保持与 2'，3'-cGAMP 相似的诱导人 THP1 细胞 IFN-β分泌的效力。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核酸酶介导的脆弱性开辟了一条新策略，作为癌症治疗剂和疫苗佐剂具有高转化潜力的额外益处。
