State Key Laboratory of Elemento-Organic Chemistry, Department of Chemical Biology, College of Chemistry, Nankai University, Tianjin 300071, China.
Frontiers Science Center for New Organic Matter, Nankai University, Tianjin 300071, China.
Int J Mol Sci. 2023 Dec 20;25(1):86. doi: 10.3390/ijms25010086.
To improve the chemical regulation on the activity of cyclic dinucleotides (CDNs), we here designed a reduction-responsive dithioethanol (DTE)-based dCDN prodrug (DTE-dCDN). Prodrug improved the cell permeability with the intracellular levels peaking in 2 h in THP-1 cells. Under the reductive substance such as GSH or DTT, prodrug could be quickly decomposed in 30 min to release the parent dCDN. In THP1-Lucia cells, prodrug also retained a high bioactivity with the EC of 0.96 μM, which was 51-, 43-, and 3-fold more than the 2',3'-cGAMP (EC = 48.6 μM), the parent compound 3',3'-c-di-dAMP (EC = 41.3 μM), and ADU-S100 (EC = 2.9 μM). The high bioactivity of prodrug was validated to be highly correlated with the activation of the STING signaling pathway. Furthermore, prodrug could also improve the transcriptional expression levels of , , and in THP-1 cells. These results will be helpful to the development of chemically controllable CDN prodrugs with a high cellular permeability and potency.
为了提高环状二核苷酸（CDNs）的化学调控活性，我们设计了一种基于还原响应性二硫乙醇（DTE）的 dCDN 前药（DTE-dCDN）。前药提高了细胞通透性，在 THP-1 细胞中 2 小时内达到细胞内浓度峰值。在 GSH 或 DTT 等还原物质存在的情况下，前药可以在 30 分钟内迅速分解，释放出母体 dCDN。在 THP1-Lucia 细胞中，前药也保持了高生物活性，EC 值为 0.96 μM，是 2'，3'-cGAMP（EC = 48.6 μM）、母体化合物 3'，3'-c-di-dAMP（EC = 41.3 μM）和 ADU-S100（EC = 2.9 μM）的 51、43 和 3 倍。前药的高生物活性被证实与 STING 信号通路的激活高度相关。此外，前药还可以提高 THP-1 细胞中 、 、 和 的转录表达水平。这些结果将有助于开发具有高细胞通透性和效力的化学可控 CDN 前药。
