The cGAS-STING pathway is a crucial part of innate immunity; it serves to detect DNA in the cytoplasm and to defend against certain cancers, viruses, and bacteria. We designed and synthesized fluorinated carbocyclic cGAMP analogs, MD1203 and MD1202D (MDs), to enhance their stability and their affinity for STING. These compounds demonstrated exceptional activity against STING. Despite their distinct chemical modifications relative to the canonical cyclic dinucleotides (CDNs), crystallographic analysis revealed a binding mode with STING that was consistent with the canonical CDNs. Importantly, MDs were resistant to cleavage by viral poxin nucleases and MDs-bound poxin adopted an unliganded-like conformation. Moreover, MDs complexed with poxin showed a conformation distinct from cGAMP bound to poxin, closely resembling their conformation when bound to STING. In conclusion, the development of MD1203 and MD1202D showcases their potential as potent STING activators with remarkable stability against poxin-mediated degradation—a crucial characteristic for future development of antivirals.

中文翻译：

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氟化 cGAMP 类似物，作为 STING 激动剂，不能被痘病毒裂解：其功能的结构基础


cGAS-STING 通路是先天免疫的重要组成部分；它用于检测细胞质中的 DNA 并防御某些癌症、病毒和细菌。我们设计并合成了氟化碳环 cGAMP 类似物 MD1203 和 MD1202D (MD)，以增强其稳定性和对 STING 的亲和力。这些化合物表现出卓越的抗 STING 活性。尽管它们相对于规范的环状二核苷酸 (CDN) 有不同的化学修饰，但晶体分析揭示了与 STING 的结合模式与规范的 CDN 一致。重要的是，MD 能够抵抗病毒痘蛋白核酸酶的切割，并且与 MD 结合的痘蛋白采用未配体样构象。此外，与痘蛋白复合的MD表现出与与痘蛋白结合的cGAMP不同的构象，与它们与STING结合时的构象非常相似。总之，MD1203 和 MD1202D 的开发展示了它们作为有效的 STING 激活剂的潜力，对痘蛋白介导的降解具有显着的稳定性——这是未来抗病毒药物开发的一个关键特征。