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Design, synthesis and biological evaluation of acridone analogues as novel STING receptor agonists.
Bioorganic Chemistry ( IF 4.5 ) Pub Date : 2019-12-30 , DOI: 10.1016/j.bioorg.2019.103556
Shi Hou 1 , Xiu-Juan Lan 1 , Wei Li 2 , Xin-Lin Yan 2 , Jia-Jia Chang 3 , Xiao-Hong Yang 4 , Wei Sun 4 , Jun-Hai Xiao 2 , Song Li 2
Affiliation  

STING (Stimulator of Interferon Genes) has become a focal point in immunology research and a target in drug discovery. The discovery of a potent human-STING agonist is expected to revolutionize current anti-virus or cancer immunotherapy. Inspired by the structure and function of murine STING-specific agonists (DMXAA and CMA), we rationally designed and synthesized four series of novel compounds for the enhancement of human sensitivity. In the cell-based assay, we identified six compounds from all the synthetic small molecules: 2g, 9g, and 12b are STING agonists that are efficacious across species, and all have the skeleton of acridone; 1b, 1c, and 12c just function in the murine STING pathway. Notably, 12b exhibits the best activity among the six agonists, and its inductions of both human and murine STING-dependent signalling are similar to that of 2'3'-cGAMP, which is a well-known STING inducer. While a protein assay indicated that 2 g, 9 g, and 12b could activate the pathway by directly binding human STING, 12b also displayed the strongest binding affinity. Additionally, our studies show that 12b can induce faster, more powerful, and more durable responses of assorted cytokines in a native system than 2'3'-cGAMP. Consequently, our team is the first to successfully modify murine STING agonists to obtain human sensitivity, and these results suggest that 12b is a potent direct-human-STING agonist. Additionally, the acridone analogues demonstrate tremendous potential in the treatment of tumours or viral infections.

中文翻译:

cri啶酮类似物作为新型STING受体激动剂的设计,合成和生物学评估。

STING(干扰素基因的刺激物)已成为免疫学研究的重点和药物发现的目标。有望发现有效的人类STING激动剂,将彻底改变当前的抗病毒或癌症免疫疗法。受鼠STING特异性激动剂(DMXAA和CMA)的结构和功能的启发,我们合理设计和合成了四组新化合物以增强人类敏感性。在基于细胞的分析中,我们从所有合成的小分子中鉴定出六种化合物:2g,9g和12b是STING激动剂,在整个物种中均有效,并且都具有a啶酮的骨架。1b,1c和12c仅在鼠STING途径中起作用。值得注意的是,12b在六种激动剂中表现出最好的活性,其对人和鼠STING依赖性信号转导的诱导作用均与众所周知的STING诱导剂2'3'-cGAMP相似。蛋白质分析表明2 g,9 g和12b可通过直接结合人STING激活该途径,而12b也显示出最强的结合亲和力。此外,我们的研究表明,与2'3'-cGAMP相比,在天然系统中12b可以诱导更快,更强大和更持久的各种细胞因子应答。因此,我们的团队是第一个成功修饰鼠STING激动剂以获得人类敏感性的人,这些结果表明12b是有效的直接人STING激动剂。此外,the啶酮类似物在肿瘤或病毒感染的治疗中显示出巨大的潜力。蛋白质分析表明2 g,9 g和12b可通过直接结合人STING激活该途径,而12b也显示出最强的结合亲和力。此外,我们的研究表明,与2'3'-cGAMP相比,在天然系统中12b可以诱导更快,更强大和更持久的各种细胞因子应答。因此,我们的团队是第一个成功修饰鼠STING激动剂以获得人类敏感性的人,这些结果表明12b是有效的直接人STING激动剂。此外,the啶酮类似物在肿瘤或病毒感染的治疗中显示出巨大的潜力。蛋白质分析表明2 g,9 g和12b可通过直接结合人STING激活该途径,而12b也显示出最强的结合亲和力。此外,我们的研究表明,与2'3'-cGAMP相比,在天然系统中12b可以诱导更快,更强大和更持久的各种细胞因子应答。因此,我们的团队是第一个成功修饰鼠STING激动剂以获得人类敏感性的人,这些结果表明12b是有效的直接人STING激动剂。此外,the啶酮类似物在肿瘤或病毒感染的治疗中显示出巨大的潜力。与2'3'-cGAMP相比,天然系统中各种细胞因子的反应更强大,更持久。因此,我们的团队是第一个成功修饰鼠STING激动剂以获得人类敏感性的人,这些结果表明12b是有效的直接人STING激动剂。此外,the啶酮类似物在肿瘤或病毒感染的治疗中显示出巨大的潜力。与2'3'-cGAMP相比,天然系统中各种细胞因子的反应更强大,更持久。因此,我们的团队是第一个成功修饰鼠STING激动剂以获得人类敏感性的人,这些结果表明12b是有效的直接人STING激动剂。此外,the啶酮类似物在肿瘤或病毒感染的治疗中显示出巨大的潜力。
更新日期:2019-12-31
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