Dithioethanol (DTE)-Conjugated Deoxyribose Cyclic Dinucleotide Prodrugs (DTE-dCDNs) as STING Agonist
To improve the chemical regulation on the activity of cyclic dinucleotides (CDNs), we here designed a reduction-responsive dithioethanol (DTE)-based dCDN prodrug <b>9</b> (DTE-dCDN). Prodrug <b>9</b> improved the cell permeability with the intracellular levels peaking in 2 h...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-12-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/25/1/86 |
| Summary: | To improve the chemical regulation on the activity of cyclic dinucleotides (CDNs), we here designed a reduction-responsive dithioethanol (DTE)-based dCDN prodrug <b>9</b> (DTE-dCDN). Prodrug <b>9</b> 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 <b>9</b> could be quickly decomposed in 30 min to release the parent dCDN. In THP1-Lucia cells, prodrug <b>9</b> also retained a high bioactivity with the EC<sub>50</sub> of 0.96 μM, which was 51-, 43-, and 3-fold more than the 2′,3′-cGAMP (EC<sub>50</sub> = 48.6 μM), the parent compound 3′,3′-c-di-dAMP (EC<sub>50</sub> = 41.3 μM), and ADU-S100 (EC<sub>50</sub> = 2.9 μM). The high bioactivity of prodrug <b>9</b> was validated to be highly correlated with the activation of the STING signaling pathway. Furthermore, prodrug <b>9</b> could also improve the transcriptional expression levels of <i>IFN-β</i>, <i>CXCL10</i>, <i>IL-6,</i> and <i>TNF-α</i> in THP-1 cells. These results will be helpful to the development of chemically controllable CDN prodrugs with a high cellular permeability and potency. |
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| ISSN: | 1661-6596 1422-0067 |