diABZI STING agonist-1 trihydrochloride, as a STING agonist, is internalized into the cytoplasm through unknown receptor and induce the activation and dimerization of STING followed by TBK1/IRF3 phosporylation leading to type I IFN response.[2]
diABZI STING agonist-1 trihydrochloride can activate STING and has an effictively effect in limiting SARS-CoV-2 replication in cells and animals.[1]
In vitro, diABZI dose dependently protected the cells from CPEs with an EC50 value of 3 nM, suggesting the significant anti-HCoV-229E activity comparable to that of Remdesivir (RDV, EC50 = 26 nM). Furthermore, the half maximal cytotoxic concentration value (CC50) of diABZI was greater than 100 μM in MRC-5 cells, indicating that the observed antiviral effects were not related to nonspecific cytotoxicity.[3]
In vitro, treatment with 0.1 μM diABZI-4 in CD14+ human monocytes it shown that diABZI-4 (STING agonist) induced oligomerization of STING, transcription of IFNB1, TNF, CXCL10 and IL6 and the secretion of TNF-α and IFN-βin primary human CD14+ monocytes. In the meanwhile, 0.1 μM of diABZI-4 also inhibits SARS-CoV-2 replication in lung epithelial cells. [1] In vitro efficacy test, treatment with 1?μM DiABZI induced the release of IFNα, IFNβ, CXCL10, IL-6, TNFα, CXCL1, and IL-10 at 16?h. Treatment with 1–10?μM DiABZI induced the expression of IFNβ, IL-1β, and IL-8. In addition, DiABZI at 0.3–1?μM induced the phosphorylation of STING and downstream TBK1 kinase, together with STAT1 phosphorylation, similar to cGAMP.[2]
In vivo experiment it indicated that after endotracheal administration of 0.1–1?μg diABZI, STING overexpression and activation visible by increased STING dimers in immunoblots of lung tissue.
References:
[1].Humphries F, et al. A diamidobenzimidazole STING agonist protects against SARS-CoV-2 infection. Sci Immunol. 2021 May 18;6(59):eabi9002.
[2].Messaoud-Nacer Y, et al. STING agonist diABZI induces PANoptosis and DNA mediated acute respiratory distress syndrome (ARDS). Cell Death Dis. 2022 Mar 25;13(3):269.
[3].Zhu Q, et al. Inhibition of coronavirus infection by a synthetic STING agonist in primary human airway system. Antiviral Res. 2021 Mar;187:105015.
diABZI STING agonist-1 trihydrochloride 作为一种 STING 激动剂，通过未知受体内化到细胞质中并诱导 STING 的激活和二聚化，然后是 TBK1/IRF3 磷酸化，从而导致 I 型 IFN 反应。[2]
diABZI STING agonist-1 trihydrochloride 可激活 STING，并有效限制 SARS-CoV-2 在细胞和动物中的复制。[1]
在体外，diABZI 剂量依赖性地保护细胞免受 CPE 的影响，EC50 值为 3 nM，这表明其显着的抗 HCoV-229E 活性可与 Remdesivir（RDV，EC50 = 26 nM）相媲美。此外，diABZI 在 MRC-5 细胞中的半数最大细胞毒性浓度值 (CC50) 大于 100 μM，表明观察到的抗病毒作用与非特异性细胞毒性无关。[3]
在体外，用 0.1 μM diABZI-4 处理 CD14+ 人单核细胞表明 diABZI-4（STING 激动剂）诱导 STING 的寡聚化、IFNB1、TNF、CXCL10 和 IL6 的转录以及 TNF-α 和 IFN 的分泌-β 在原代人 CD14+ 单核细胞中。同时，0.1 μM 的 diABZI-4 也抑制 SARS-CoV-2 在肺上皮细胞中的复制。 [1] 体外药效试验，1μM DiABZI 处理在 16h 诱导 IFNα、IFNβ、CXCL10、IL-6、TNFα、CXCL1 和 IL-10 的释放。用 1-10μM DiABZI 处理可诱导 IFNβ、IL-1β 和 IL-8 的表达。此外，0.3-1μM 的 DiABZI 诱导 STING 和下游 TBK1 激酶的磷酸化，以及 STAT1 磷酸化，类似于 cGAMP。[2]
体内实验表明，气管内给予 0.1-1μg diABZI 后，肺组织免疫印迹中 STING 二聚体增加可见 STING 过表达和激活。