Department of Chemistry, 560 Oval Drive, West Lafayette, Indiana, 47907-2084.
Institute for Drug Discovery, Purdue University, 720 Clinic Drive, West Lafayette, IN 47907, USA.
Chembiochem. 2024 Jul 2;25(13):e202400321. doi: 10.1002/cbic.202400321. Epub 2024 Jun 21.
Cyclic dinucleotides (CDNs) have garnered popularity over the last decade as immunotherapeutic agents, which activate the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway to trigger an immune response. Many analogs of 2'3'-cGAMP, c-di-GMP, and c-di-AMP have been developed and shown as effective cancer vaccines and immunomodulators for the induction of both the adaptive and innate immune systems. Unfortunately, the effectiveness of these CDNs is limited by their chemical and enzymatic instability. We recently introduced 5'-endo-phosphorothoiate 2'3'-cGAMP analogs as potent STING agonist with improved resistance to cleavage by clinically relevant phosphodiesterases. We herein report the synthesis of locked nucleic acid-functionalized (LNA) endo-S-CDNs and evaluate their ability to activate STING in THP1 monocytes. Interestingly, some of our synthesized LNA 3'3'-endo-S-CDNs can moderately activate hSTING REF haplotype (R232H), which exhibit diminished response to both 2'3'-cGAMP and ADU-S100. Also, we show that one of our most potent endo-S-CDNs has remarkable chemical (oxidants I and HO) and phosphodiesterase stability.
环状二核苷酸 (CDNs) 在过去十年中作为免疫治疗剂越来越受欢迎，它们激活环鸟苷酸-腺苷酸合酶-干扰素基因刺激物 (cGAS-STING) 途径以触发免疫反应。已经开发出许多 2'3'-cGAMP、c-di-GMP 和 c-di-AMP 的类似物，并已被证明是有效的癌症疫苗和免疫调节剂，可诱导适应性和固有免疫系统。不幸的是，这些 CDNs 的有效性受到其化学和酶不稳定性的限制。我们最近引入了 5'-末端膦硫代 2'3'-cGAMP 类似物作为有效的 STING 激动剂，对临床相关磷酸二酯酶的切割具有更高的抗性。在此，我们报告了锁核酸 (LNA) 功能化的内消旋 5'-endo-硫代磷酸酯 CDNs 的合成，并评估了它们在 THP1 单核细胞中激活 STING 的能力。有趣的是，我们合成的一些 LNA 3'3'-endo-S-CDNs 可以适度激活 hSTING REF 单倍型 (R232H)，其对 2'3'-cGAMP 和 ADU-S100 的反应均减弱。此外，我们表明，我们最有效的内消旋 S-CDN 之一具有显著的化学（氧化剂 I 和 HO）和磷酸二酯酶稳定性。
