Home>>Signaling Pathways>> Immunology/Inflammation>> STING>>diABZI STING agonist-1 trihydrochloride

diABZI STING agonist-1 trihydrochloride Sale

(Synonyms: Diamidobenzimidazole STING Agonist-1, STING Agonist (Compound 3), STING Agonist diABZI) 目录号 : GC35855

diABZI STING agonist-1 (trihydrochloride) 是干扰素基因 (STING) 受体激动剂的选择性刺激剂,对人和小鼠的 EC50 分别为 130 和 186 nM。

diABZI STING agonist-1 trihydrochloride Chemical Structure

Cas No.:2138299-34-8

规格 价格 库存 购买数量
10mM (in 1mL DMSO)
¥5,603.00
现货
1mg
¥1,543.00
现货
5mg
¥3,150.00
现货
10mg
¥5,310.00
现货

电话:400-920-5774 Email: sales@glpbio.cn

Customer Reviews

Based on customer reviews.

Sample solution is provided at 25 µL, 10mM.

产品文档

Quality Control & SDS

View current batch:

实验参考方法

Cell experiment [1]:

Cell lines

MRC-5 cells

Preparation Method

0.1, 1, 10 μM diABZI, or RDV, or DMSO as a control was added to the basolateral chamber of the ALI, followed by apical challenge with SARS-CoV-2 (Beta CoV/France/IDF0571/2020 strain) challenge apically.The viral RNA collected from apical washes at 48 h and 72 h hpi was quantified, and disruption of the epithelial layer was measured as TEER.

Reaction Conditions

0.1, 1, 10 μM, at 48 h and 72 h

Applications

diABZI in all tested concentration range potently decreased the level of SARS-CoV-2 viral RNA in a dose-dependent manner. Treatment with diABZI at the concentration as low as 0.1 μM fully protected the integrity of the epithelial layer in the ALI model from SARS-CoV-2 challenge.

Animal experiment [2]:

Animal models

Female C57BL/6Rj mice

Preparation Method

STING agonist diABZI (0.01, 0.1, or 1 µg, i.t.) DMSO (0.25%) vehicle or saline were administered daily in WT mice for 3 consecutive days and parameters were analyzed on day 4. Concentration of CXCL1/KC in the bronchoalveolar lavage fluid (BALF) determined by ELISA.

Dosage form

0.01, 0.1, or 1 µg, i.t.

Applications

Endotracheal administration of diABZI for 3 consecutive days induced a strong airway inflammation within 24 h. CXCL1 was released in the bronchoalveolar space after 0.1–1 µg diABZI administration

References:

[1].Zhu Q, et al. Inhibition of coronavirus infection by a synthetic STING agonist in primary human airway system. Antiviral Res. 2021 Mar;187:105015.

[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.

产品描述

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]

\n

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。

Chemical Properties

Cas No. 2138299-34-8 SDF
别名 Diamidobenzimidazole STING Agonist-1, STING Agonist (Compound 3), STING Agonist diABZI
Canonical SMILES O=C(N)C1=CC(N=C(NC(C2=CC(C)=NN2CC)=O)N3C/C=C/CN4C(NC(C5=CC(C)=NN5CC)=O)=NC6=C4C(OCCCN7CCOCC7)=CC(C(N)=O)=C6)=C3C(OC)=C1.Cl.Cl.Cl
分子式 C42H54Cl3N13O7 分子量 959.32
溶解度 DMSO: 125 mg/mL (130.30 mM) 储存条件 Store at -20°C
General tips 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液;一旦配成溶液,请分装保存,避免反复冻融造成的产品失效。
储备液的保存方式和期限:-80°C 储存时,请在 6 个月内使用,-20°C 储存时,请在 1 个月内使用。
为了提高溶解度,请将管子加热至37℃,然后在超声波浴中震荡一段时间。
Shipping Condition 评估样品解决方案:配备蓝冰进行发货。所有其他可用尺寸:配备RT,或根据请求配备蓝冰。

溶解性数据

制备储备液
1 mg 5 mg 10 mg
1 mM 1.0424 mL 5.212 mL 10.4241 mL
5 mM 0.2085 mL 1.0424 mL 2.0848 mL
10 mM 0.1042 mL 0.5212 mL 1.0424 mL
  • 摩尔浓度计算器

  • 稀释计算器

  • 分子量计算器

质量
=
浓度
x
体积
x
分子量
 
 
 
*在配置溶液时,请务必参考产品标签上、MSDS / COA(可在Glpbio的产品页面获得)批次特异的分子量使用本工具。

计算

动物体内配方计算器 (澄清溶液)

第一步:请输入基本实验信息(考虑到实验过程中的损耗,建议多配一只动物的药量)
给药剂量 mg/kg 动物平均体重 g 每只动物给药体积 ul 动物数量
第二步:请输入动物体内配方组成(配方适用于不溶于水的药物;不同批次药物配方比例不同,请联系GLPBIO为您提供正确的澄清溶液配方)
% DMSO % % Tween 80 % saline
计算重置

Research Update

STING agonist diABZI induces PANoptosis and DNA mediated acute respiratory distress syndrome (ARDS)

Cell Death Dis2022 Mar 25;13(3):269.PMID: 35338116DOI: 10.1038/s41419-022-04664-5

Stimulator of interferon genes (STING) contributes to immune responses against tumors and may control viral infection including SARS-CoV-2 infection. However, activation of the STING pathway by airway silica or smoke exposure leads to cell death, self-dsDNA release, and STING/type I IFN dependent acute lung inflammation/ARDS. The inflammatory response induced by a synthetic non-nucleotide-based diABZI STING agonist, in comparison to the natural cyclic dinucleotide cGAMP, is unknown. A low dose of diABZI (1 µg by endotracheal route for 3 consecutive days) triggered an acute neutrophilic inflammation, disruption of the respiratory barrier, DNA release with NET formation, PANoptosis cell death, and inflammatory cytokines with type I IFN dependent acute lung inflammation. Downstream upregulation of DNA sensors including cGAS, DDX41, IFI204, as well as NLRP3 and AIM2 inflammasomes, suggested a secondary inflammatory response to dsDNA as a danger signal. DNase I treatment, inhibition of NET formation together with an investigation in gene-deficient mice highlighted extracellular DNA and TLR9, but not cGAS, as central to diABZI-induced neutrophilic response. Therefore, activation of acute cell death with DNA release may lead to ARDS which may be modeled by diABZI. These results show that airway targeting by STING activator as a therapeutic strategy for infection may enhance lung inflammation with severe ARDS. STING agonist diABZI induces neutrophilic lung inflammation and PANoptosis A, Airway STING priming induce a neutrophilic lung inflammation with epithelial barrier damage, double-stranded DNA release in the bronchoalvelolar space, cell death, NETosis and type I interferon release. B, 1. The diamidobenzimidazole (diABZI), 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. STING activation also leads to NF-kB activation and the production of pro-inflammatory cytokines TNFα and IL-6. 2. The activation of TNFR1 and IFNAR1 signaling pathway results in ZBP1 and RIPK3/ASC/CASP8 activation leading to MLKL phosphorylation and necroptosis induction. 3. This can also leads to Caspase-3 cleavage and apoptosis induction. 4. Self-dsDNA or mtDNA sensing by NLRP3 or AIM2 induces inflammsome formation leading to Gasdermin D cleavage enabling Gasdermin D pore formation and the release mature IL-1β and pyroptosis. NLRP3 inflammasome formation can be enhanced by the ZBP1/RIPK3/CASP8 complex. 5. A second signal of STING activation with diABZI induces cell death and the release of self-DNA which is sensed by cGAS and form 2'3'-cGAMP leading to STING hyper activation, the amplification of TBK1/IRF3 and NF-kB pathway and the subsequent production of IFN-I and inflammatory TNFα and IL-6. This also leads to IFI204 and DDX41 upregulation thus, amplifying the inflammatory loop. The upregulation of apoptosis, pyroptosis and necroptosis is indicative of STING-dependent PANoptosis.

A diamidobenzimidazole STING agonist protects against SARS-CoV-2 infection

Sci Immunol2021 May 18;6(59):eabi9002.PMID: 34010139DOI: 10.1126/sciimmunol.abi9002

Coronaviruses are a family of RNA viruses that cause acute and chronic diseases of the upper and lower respiratory tract in humans and other animals. SARS-CoV-2 is a recently emerged coronavirus that has led to a global pandemic causing a severe respiratory disease known as COVID-19 with significant morbidity and mortality worldwide. The development of antiviral therapeutics are urgently needed while vaccine programs roll out worldwide. Here we describe a diamidobenzimidazole compound, diABZI-4, that activates STING and is highly effective in limiting SARS-CoV-2 replication in cells and animals. diABZI-4 inhibited SARS-CoV-2 replication in lung epithelial cells. Administration of diABZI-4 intranasally before or even after virus infection conferred complete protection from severe respiratory disease in K18-ACE2-transgenic mice infected with SARS-CoV-2. Intranasal delivery of diABZI-4 induced a rapid short-lived activation of STING, leading to transient proinflammatory cytokine production and lymphocyte activation in the lung associated with inhibition of viral replication. Our study supports the use of diABZI-4 as a host-directed therapy which mobilizes antiviral defenses for the treatment and prevention of COVID-19.

Pharmacological activation of STING blocks SARS-CoV-2 infection

Sci Immunol2021 May 18;6(59):eabi9007.PMID: 34010142DOI: 10.1126/sciimmunol.abi9007

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic, resulting millions of infections and deaths with few effective interventions available. Here, we demonstrate that SARS-CoV-2 evades interferon (IFN) activation in respiratory epithelial cells, resulting in a delayed response in bystander cells. Since pretreatment with IFNs can block viral infection, we reasoned that pharmacological activation of innate immune pathways could control SARS-CoV-2 infection. To identify potent antiviral innate immune agonists, we screened a panel of 75 microbial ligands that activate diverse signaling pathways and identified cyclic dinucleotides (CDNs), canonical STING agonists, as antiviral. Since CDNs have poor bioavailability, we tested the small molecule STING agonist diABZI, and found that it potently inhibits SARS-CoV-2 infection of diverse strains including variants of concern (B.1.351) by transiently stimulating IFN signaling. Importantly, diABZI restricts viral replication in primary human bronchial epithelial cells and in mice in vivo. Our study provides evidence that activation of STING may represent a promising therapeutic strategy to control SARS-CoV-2.

Design of amidobenzimidazole STING receptor agonists with systemic activity

Nature2018 Dec;564(7736):439-443.PMID: 30405246DOI: 10.1038/s41586-018-0705-y

Stimulator of interferon genes (STING) is a receptor in the endoplasmic reticulum that propagates innate immune sensing of cytosolic pathogen-derived and self DNA1. The development of compounds that modulate STING has recently been the focus of intense research for the treatment of cancer and infectious diseases and as vaccine adjuvants2. To our knowledge, current efforts are focused on the development of modified cyclic dinucleotides that mimic the endogenous STING ligand cGAMP; these have progressed into clinical trials in patients with solid accessible tumours amenable to intratumoral delivery3. Here we report the discovery of a small molecule STING agonist that is not a cyclic dinucleotide and is systemically efficacious for treating tumours in mice. We developed a linking strategy to synergize the effect of two symmetry-related amidobenzimidazole (ABZI)-based compounds to create linked ABZIs (diABZIs) with enhanced binding to STING and cellular function. Intravenous administration of a diABZI STING agonist to immunocompetent mice with established syngeneic colon tumours elicited strong anti-tumour activity, with complete and lasting regression of tumours. Our findings represent a milestone in the rapidly growing field of immune-modifying cancer therapies.

Molecular Dynamics Simulations Reveal the Modulated Mechanism of STING Conformation

Interdiscip Sci2021 Dec;13(4):751-765.PMID: 34142362DOI: 10.1007/s12539-021-00446-3

Stimulator of interferon genes (STING), which is an integral ER-membrane protein, could induce an antiviral state and boost antitumor immunity. Recent experiments reported that different small molecules could modulate the conformation of the STING. However, the mechanism of small molecules modulating the conformation of STING is still unknown. To illustrate the conformational modulated mechanism of STING by small molecules at atomic level, we investigated the interactions between STING and the small molecules: cGAMP and diABZI with molecular dynamics (MD) simulations method. Interestingly, we found that the residues of STING in the binding pocket are more flexible in the monomers of STING than that in the dimer of STING. We also demonstrated that cGAMP and diABZI have a similar binding mode to STING monomers/dimer, and π-π stacking interactions play important roles for the agonists and STING. Our study proposed mechanistic insights into the STING conformation modulated by small molecules and we suggested that the special molecule (e. g. diABZI) could induce the conformational transition of STING from the "open" monomers to the "closed" dimer state. Our research may provide a clue for the development of cancer immunotherapy.