阿拉伯糖和木糖修饰的2'，3'-cGAMP类似物作为STING激动剂。
Arabinose- and xylose-modified analogs of 2',3'-cGAMP act as STING agonists.
发表日期：2023 Jul 25
作者：
Wei Xie, Lodoe Lama, Xuejing Yang, Vitaly Kuryavyi, Shibani Bhattacharya, Ilona Nudelman, Guangli Yang, Ouathek Ouerfelli, J Fraser Glickman, Roger A Jones, Thomas Tuschl, Dinshaw J Patel
来源：
CLINICAL PHARMACOLOGY & THERAPEUTICS
摘要：
核酸激活因子刺激剂（STING激动剂）是作为疫苗佐剂和抗肿瘤免疫刺激剂的有希望的候选物。STING最有效的天然激动剂2',3'-环磷酸鸟苷酸（2',3'-cGAMP）易受核酸酶介导的内在代谢不稳定性的影响，从而限制了其临床疗效。在这里，我们报告一类新的化学合成的2',3'-cGAMP的糖修饰类似物，包含阿拉伯糖和木糖糖衍生物，这些类似物与小鼠和人类STING等位基因具有高亲和性。共结晶结构证明这些类似物作为2',3'-cGAMP的模拟物，诱导了人类STING的“闭合”构象。这些类似物在人体血清中表现出明显的对ENPP1介导的水解的抵抗能力，并保持从人类THP1细胞中诱导IFN-β分泌的类似效力。阿拉伯糖和木糖修饰的2',3'-cGAMP类似物开辟了一种新的策略，以克服天然核酸背骨环状核苷酸易受核酸酶介导脆弱性的困境，同时具有高转化潜力作为抗癌治疗药物和疫苗佐剂。版权所有 © 2023 Elsevier Ltd. 保留所有权利。
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.Copyright © 2023 Elsevier Ltd. All rights reserved.