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2',3'-cGAMP的阿拉比诺斯和西洛斯修饰的类似物作为STING激动剂起作用

Wei Xie¹, Lodoe Lama², Xuejing Yang³

¹Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.

Cell chemical biology

|August 3, 2023

概括

化学合成的2',3'-循环GMP-AMP (2',3'-cGAMP) 的糖改性类似物克服了核酶的不稳定性. 这些新型的刺痛激动剂显示出作为癌症治疗药物和疫苗辅助剂的前景.

科学领域:

免疫学免疫学免疫学
药用化学医学化学
结构生物学结构生物学

背景情况:

干扰素基因刺激剂 (STING) 激动剂对于疫苗辅助剂和抗瘤疗法至关重要.
自然的STING激动剂,2",3"-循环GMP-AMP (2",3"-cGAMP),由于核酶而表现出代谢不稳定性,限制了其临床使用.

研究的目的:

开发具有增强代谢稳定性和保留STING激动活性的新型2",3"-cGAMP类似物.
调查这些同类物与STING的相互作用的结构基础.

主要方法:

用阿拉比诺斯和克西洛斯修饰的2",3"-cGAMP类似物进行化学合成.
对老鼠和人类的STING等位基因进行绑定亲和测试.
对STING-模拟复合物的共同晶体结构的确定.
对ENPP1水解的耐药性和人类血清稳定性的评估.
在人类THP1细胞中测量IFN-β分泌.

主要成果:

合成的糖改性类似物以高亲和力结合小鼠和人类的STING.
共同晶体结构显示类似物模仿2",3"-cGAMP并诱导一个封闭的STING形状.
类似物体对ENPP1水解的抗性增加,血清稳定性提高.
修改后的类似物在诱导IFN-β分泌方面保持强度,相当于2",3"-cGAMP.

结论:

氨酸和氨酸修饰的2",3"-cGAMP类似物代表了克服循环核酸核酶介导不稳定的新策略.
由于稳定性提高和有效性保持,这些类似物提供了作为癌症治疗药物和疫苗辅助剂的显著翻译潜力.

关键词:

2′,3′-cGAMPP的2′,3′-cGAMP的2′,3′-cGAMP的2′,3′-cGAMP的2′,3′-cGAMP的2′,3′-cGAMP的2′,3′-cGAMP的2′,3′-cGAMP的2′,3′-cGAMP的针对STING的类似产品阿拉比诺和西洛的类似物.癌症治疗方法癌症治疗方法对ENPP1的抗性.人类血清中的稳定性疫苗辅助剂疫苗辅助剂

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