Inhibition of coronavirus infection by a synthetic sting agonist in primary human airway system. Here, we demonstrate that the NRF2 .

Inhibition of coronavirus infection by a synthetic sting agonist in primary human airway system May 28, 2021 · 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. Therefore, our study identifies the STING signaling pathway as an important therapeutic target that could be specifically activated for hampering infection of SARS-CoV-2 and other coronaviruses. These innate immune responses not only limit the Jul 22, 2021 · This new platform model for infection with coronaviruses represents an important new capability for studying coronavirus infections in human primary lung tissue and evaluating therapeutics Sep 1, 2023 · As the first line of defense against invasion by exogenous pathogens, innate immunity is of great interest. While three subsets of interferons exist (Type I, II, and III), Type I IFNs (primarily IFNα and IFNβ) are of particular interest because nearly all nucleated cells are able to produce and Aug 1, 2022 · The binding of mis-localized dsDNA initiates cGAS activation to synthesize a noncanonical cGAMP, which diffuses and mobilizes STING for innate immune responses [23]. Domizio JD, Gulen MF, Saidoune F, Thacker VV, Yatim A, Sharma K, et al. STING proteins are transmembrane proteins located in the endoplasmic reticulum, and STING is an important signaling protein associated with the natural immune system . On the next day, Sting –/– 3D4/21 cells were transfected with plasmid for expression of STING-Flag (4 μg) for 24 h. Jun 6, 2024 · gene (STING) has an immunotherapy potential to govern a variety of infectious diseases. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently emerged coronavirus that has led to a global pandemic, causing a severe respiratory disease known as coronavirus disease 2019 (COVID Mar 30, 2022 · Previous studies reported that a STING agonist, diABZI, effectively blocks SARS-CoV-2 infection. For now, several STING agonists such as Innate immunity is the first line of defense against any invading pathogen, including SARS-CoV-2. Despite these advances STING agonist blocks SARS-CoV-2 in human primary cells and in vivo. 2023 Nov:219:105730. The innate immune system is the first line of defence against viral infection and characterized by production of type I interferons (IFN‐α and β). diABZI STING agonist-1 also decreases the level of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA in primary human bronchial airway epithelial cells in an air-liquid interface assay. diABZI STING agonist-1 also decreases the levels of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA in primary human bronchial airway epithelial cells in an air-liquid interface assay. 105730. 3 A-B), as well as MCP-1 (Supplementary Fig. Antiviral research. Activation of STING pathway may provide a new therapeutic approach fighting against these viruses. https://orcid. show that coronaviruses modulate ER stress and the unfolded protein response. Stimulator of Interferon Genes (STING) is a chief element in host antiviral defense pathways. Many favorable anticancer treatments owe their success to the induction immunogenic cell death (ICD) in cancer cells, which results in the release of endogenous danger signals along with tumor antigens for effective priming of anticancer immunity. 9A) in treated mice. Results: During the early stages of infection, the Previously the STING agonist diABZI-4, a diamidobenzimidazole-based compound, demonstrated protection against SARS-CoV-2 both in vitro and in vivo. Therefore, we first monitored STING activation in ACE2-expressing A549 cells treated with diABZI-4, Jun 3, 2024 · As a major component of innate immunity and a positive regulator of interferons, the Stimulator of interferon gene (STING) has an immunotherapy potential to govern a variety of infectious diseases. 2 It decreases tumor volume and increases (DOI: 10. Sep 20, 2021 · SARS-CoV-2 in primary human respiratory epithelial cells and in vivo in two different mouse models of infection. G10 triggers innate immune responses that involve expression of IRF3-dependent genes including type I and III interferons. Mar 25, 2022 · 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 Jun 10, 2024 · COVID-19 patients. The antiviral RNA- dependent polymerase inhibitor remdesivir reduces length of hospitalization and deaths from COVID-19 (3). Nov 7, 2023 · Human airway tracheobronchial epithelial cells isolated from airway specimens from donors without underlying lung disease were provided by Lonza, Inc. [PMC free article] 42. We discovered that dimeric amidobenzimidazole (diABZI), a synthetic small molecule STING receptor agonist, showed potent anti-coronavirus activity against both the common cold human coronavirus 229E (HCoV-229E) and SARS-CoV-2 in cell culture systems. In addition, the steroid dexame-thasone has also been approved for use in severe COVID-19 (4). ABSTRACT. About. By using the site you are agreeing to this as outlined in our privacy notice and cookie policy. PubMed Abstract | CrossRef Full Text | It inhibits the cytopathic effect of the common cold human coronavirus 229E (HCoV-229E) in infected MRC-5 cells (EC 50 = 3 nM). Furthermore, the cGAS-STING pathway Dec 13, 2022 · Stimulator of interferon gene (STING) is increasingly exploited for the potential in cancer immunotherapy, yet its mechanism of activation remains not fully understood. (A) Experimental workflow for viral infection assays using Vero E6 cells. , 2009). In this connection, it has been well-documented that STING agonists are applied to combat COVID-19. , bacteria or viruses) and “self” cells (e. This website requires cookies, and the limited processing of your personal data in order to function. Jul 7, 2019 · Discovery of a carboxamide compound that activates cGAS-STING pathway. Jul 18, 2024 · Respiratory viral infection causes fast onset of pathology, and is often compounded by vaccination-resistant variants. We also found that we could treat May 28, 2021 · Here, we describe a diamidobenzimidazole compound, diABZI-4, that activates stimulator of interferon genes (STING) and is highly effective in limiting SARS-CoV-2 replication in cells and animals. Objective: Complement hyperactivation promotes lung injury and was observed in patients suffering from Middle East respiratory syndrome-related Current preclinical approaches for testing therapeutics are expanding toward using complex in vitro models, while minimizing usage of animal models. 6, eabi9002 (2021) 18 May 2021 SCIENCE IMMUNOLOGY| RESEARCH ARTICLE 1 of 12 CORONAVIRUS A diamidobenzimidazole STING agonist protects against SARS-CoV-2 infection Fiachra Humphries1*†, Liraz Shmuel-Galia1†, Zhaozhao Jiang1, Ruth Wilson1, Philip Landis2, Sze-Ling Ng2, Krishna Mohan Parsi3, Rene May 6, 2019 · Stimulator of interferon genes (STING) is an integral ER-membrane protein that can be activated by 2′3′-cGAMP synthesized by cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS) upon binding of double-stranded DNA. In this May 4, 2021 · Coronavirus disease 2019 (COVID-19) is the latest respiratory pandemic caused by severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2). 1. PIV3, which belongs to one of the four subtypes of PIV, is endemic year-round and can cause serious viral respiratory tract disease in infants and children (Bloom et al. select article Inhibition of coronavirus infection by a synthetic STING agonist in primary human airway system. The structural dimensions are indicated in angstroms. Considering the broad expression of STING in whole body and the direct lethal effect of STING agonists on immune cells in the draining lymph node (dLN), research on the optimal way to activate STING in tumor microenvironment (TME) appears to be a promising direction. We also found that we could treat infection therapeutically against diverse strains of SARS-CoV-2, suggesting that this STING agonist may serve as a novel therapeutic strategy to combat COVID-19. Context and objective: The emerging pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has imposed significant mortality and morbidity on the world. As expected, diABZI elicited potent and transient May 5, 2021 · 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 restricts viral replication in primary human bronchial epithelial cells and in mice in vivo. (A) Kinetics and severity of diABZI-induced skin inflammation in mice with or without poly (I:C) pre-treatment. Jun 24, 2023 · The STING agonist diABZI inhibited SARS-CoV-2 infection by transiently stimulating IFN signaling; diABZI restricted viral replication in primary human bronchial epithelial cells and in mice . The diamidobenzimidazole (diABZI), a STING agonist is internalized into the cytoplasm May 3, 2024 · Whole virus-based inactivated SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide have been critical to the COVID-19 pandemic response. , Cheng J. Keywords: Coronavirus; HCoV-229E; SARS-CoV-2; STIN Jan 11, 2021 · Investigating the role of STING activation during Influenza virus (IFV) infection found that dimeric amidobenzimidazole (diABZI), a STING agonist, had substantial anti-IFV Mar 14, 2023 · In this study, we investigated the anti-coronavirus activity triggered by STING activation. diABZI-4 Inhibition of coronavirus infection by a synthetic STING agonist in primary human airway system. 13,14 In this study, using dimeric amidobenzimidazole (diABZI), a newly discovered synthetic small molecule STING receptor agonist with much higher potency than CDNs, we found that activation of STING elicits potent antiviral effects against parainfluenza virus type 3 (PIV3) and human rhinovirus 16 (HRV16), two representative respiratory viral pathogens. Activated STING induces the production of type I interferons (IFNs) and proinflammatory cytokines through STING-TBK1-IRF3/NF-κB pathway, which could be applied into the treatment of infection, Background: Coronavirus 229E (HCoV-229E), one of the causes of the common cold, exacerbates chronic obstructive pulmonary disease (COPD) and bronchial asthma. 5 h in cell lines and 8 h in mice) and induces IFNs in GA-treated cells and mouse lungs. Percent inhibition was calculated as the ratio of relative luminescence units in the presence of a specific concentration of inhibitor and the relative luminescence units in the absence of inhibitor and corrected for background luminescence as follows: percent inhibition Nov 6, 2024 · To investigate the physiological role of STING in coronavirus infec-tion, we generated two STING knockout H1299, human non‐small lung carcinoma cell lines by CRISPR (Figure S1A). Oct 8, 2024 · The intricate regulation of the cGAS-STING pathway is paramount, as aberrant activation may lead to severe autoinflammatory or autoimmune diseases (59–61). Synthetic GCs, including inhaled corticosteroids, exert anti-inflammatory effects in airway epithelium by transactivation of genes and by inhibition of proinflammatory cytokine release. Jul 23, 2024 · SARS-CoV-2-contributes to sickness and death in COVID-19 patients partly by inducing a hyper-proinflammatory immune response in the host airway. , Activation of STING signaling pathway effectively blocks human coronavirus infection. Then cells were treated with vehicle (DMSO), G10 and LPS + Nig at the indicated concentrations for a Sequence alignment of HR1 and HR2 domains in SARS-CoV and SARS-CoV-2. About Europe PMC; Preprints in Europe PMC; Funders; Joining Europe PMC; Governance Sep 24, 2020 · FIGURE S1: G10 activates porcine NF-κB signaling pathway. Aug 1, 2024 · The innate immune system is a vital component of the human body's intrinsic defenses, acting as the first line of protection against viral and bacterial intruders and holding significant importance for overall health. Each criterion was scored from 0–4, with 0 = no change and 1–4 corresponding with increasing severity. Herein, we designed a novel Oct 29, 2024 · To investigate the physiological role of STING in coronavirus infec-tion, we generated two STING knockout H1299, human non‐small lung carcinoma cell lines by CRISPR (Figure S1A). SARS-CoV-2 infects lung epithelial cells via the ACE2 receptor (). 6, eabi9002 (2021) 18 May 2021 SCIENCE IMMUNOLOGY| RESEARCH ARTICLE 1 of 12 CORONAVIRUS A diamidobenzimidazole STING agonist protects against SARS-CoV-2 infection Fiachra Humphries1*†, Liraz Shmuel-Galia1†, Zhaozhao Jiang1, Ruth Wilson1, Philip Landis2, Sze-Ling Ng2, Krishna Mohan Parsi3, Rene Here, we initially observed that idronoxil (IDX), a synthetic flavonoid closely related to daidzein, stood out among other flavonoid compounds as a potent inhibitor of STING-induced IRF3 and NF-κB transcriptional programmes upon cGAS overexpression (in HEK-STING cells), or STING-induced signalling in both human and murine cell lines (mouse L929 cells, mouse immortalised Feb 5, 2021 · Stimulator of interferon genes (STING) plays a crucial role in human innate immune system, which is gradually concerned following the emerging immunotherapy. To date numerous efficaciousvaccines have been devel- oped and rolled out (5, 6). This hyper-proinflammatory state involves Sep 20, 2021 · SARS-CoV-2 in primary human respiratory epithelial cells and in vivo in two different mouse models of infection. We previously established a HepG2 cell-derived cell line with reconstituted human cGAS-STING pathway and ISG54 promotor-driven luciferase for high throughput screening of human cGAS-STING pathway agonists 49. Zhu Q et al. It has received 20 citations till now. Serving as the primary defense mechanism, it utilizes pattern recognition receptors (PRRs) to detect viruses and bacteria, triggering intracellular Dec 8, 2022 · Europe PMC is an archive of life sciences journal literature. RESULTS Stimulator of interferon genes (STING) is an endoplasmic reticulum (ER) protein that plays a crucial role in cytosolic DNA-mediated innate immunity. RESULTS Activation of STING signaling effectively blocks human coronavirus infection. Despite the recent advances regarding vaccines against COVID-19, nontoxic novel adjuvants with the potential to enhance vaccine efficacy are urgently desired. Respiratory infections with SARS-CoV-2 can result in May 18, 2021 · Severe acute respiratory syndrome coronavirus 2 small molecule STING agonist diABZI, and found that it potently inhibits SARS-CoV-2 infection of diverse strains including variants of concern (B. Q Zhu, Y Zhang, L Wang, X Yao, D Wu, J Cheng, X Pan, H Liu, A synthetic STING agonist inhibits the replication of human parainfluenza virus 3 The STING pathway can be stimulated by cyclic dinucleotides (CDNs), leading to the type I interferons (IFN) production for immunothera Since being discovered in 2008, the STING (stimulator of interferon genes) pathway has gradually been recognized as a central and promising target for immunotherapy. Respiratory infections with SARS-CoV-2 can result in asymptomatic, mild or severe forms of a disease known as Nov 1, 2020 · Next, we sought to determine the antiviral activity of the ABZI-based STING agonists against selected subtypes of PIV and HRV. Europe PMC. Antiviral Res. 3 × 10 4 cells/well) on rat tail collagen May 24, 2021 · The COVID-19 pandemic poses a serious global health threat. STING agonist alone, but not in combination with bortezomib, also induced IL-6, IL-10 and IFNγ (Supplementary Fig. Antiviral Research 2021 | Journal article DOI: 10. Primary airway cells derived from single patient sources were first expanded on plastic in Pneumacult-Ex Plus medium (Cat No. Sep 27, 2024 · Furthermore, in primary human airway cultures, SARS-CoV-2-infected cells display markedly lower levels of STING expression, and pharmacological inhibition of STING enhances infectious virion May 18, 2021 · SARS-CoV-2 in primary human respiratory epithelial cells and in vivo in two different mouse models of infection. RESULTS Inhibition of coronavirus infection by a synthetic STING agonist in primary human airway system. We describe a strategy to artificially induce ICD by delivering the agonist of stimulator of interferon genes (STING) into tumor cells using Oct 12, 2023 · Stimulator of interferon genes (STING) is a dimeric transmembrane adapter protein that plays a key role in the human innate immune response to infection and has been therapeutically exploited for Dec 8, 2015 · Pharmacologic stimulation of innate immune processes represents an attractive strategy to achieve multiple therapeutic outcomes including inhibition of virus replication, boosting antitumor immunity, and enhancing vaccine immunogenicity. ( A ) Primary normal human bronchial epithelial (NHBE) cells cultured in submersion culture (NHBE-Submersion) were treated with diABZI (10 µM) or remdesivir (10 µM), followed by infection of SARS-CoV-2 Inhibition of coronavirus infection by a synthetic STING agonist in primary human airway system. 2021, 187, Aug 5, 2021 · options for patients with COVID-19. Pattern recognition receptors (PRRs) activate the host immune system against various pathogens by detecting pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Recent studies have shown that the abnormalities and/or dysfunctions of cGAS-STING signaling are closely Sep 17, 2020 · A synthetic STING agonist inhibits the replication of human parainfluenza virus 3 and rhinovirus 16 through distinct mechanisms. Importantly, diABZI restricts viral replication in primary human bronchial May 24, 2021 · The COVID-19 pandemic poses a serious global health threat. May 2, 2023 · The SARS-CoV-2 papain-like protease (PLpro), which has deubiquitinating activity, suppresses the type I interferon (IFN-I) antiviral response. As of January 2021, the recently emerged severe-acute respiratory syndrome coronavirus 2 has led to over 2 million deaths and over 100 million infections globally (). As shown in Figure 1B, STING knockout cells exhibited increased susceptibility to coronavirus infection, as evidenced by the elevated expression levels Feb 1, 2023 · STING proteins are located in the endoplasmic reticulum (ER) and function as a symmetric dimer that can be activated by cytosolic DNA species (Fig. , Gao L. Sign in | Create an account. abi9002 [PMC free article] [Google Scholar] 68. g. Dec 6, 2022 · 27. In HEK392T cells, PLpro removed K63-linked polyubiquitin chains from Lys 289 of the stimulator of interferon genes (STING). Type I IFNs are secreted cytokines that include IFN-β and multiple IFN-α subtypes that engage the IFN-α/β receptor (IFNAR) present on nearly all cells (). Screening of the NCI Diversity Set V collection of 1,594 small Feb 1, 2022 · Ubc13-catalyzed K63 ubiquitination is a major control point for immune signaling. May 18, 2021 · We found that diABZI was active against SARS-CoV-2 in primary human respiratory epithelial cells and in vivo in two different mouse models of infection. Sci Immunol (2021) 6:eabi9002. Double-stranded DNA (dsDNA) in the cytoplasm, which can be derived from pathogens (e. Menu. Here, we demonstrate that the NRF2 Mar 25, 2022 · 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. Authors This "Cited by" count includes citations to the following articles in Scholar. A synthetic STING agonist inhibits the replication are among the leading causes of respiratory infections that affect human health without effective treatments. 1, 2 DNA is an important PAMP, and Apr 21, 2023 · The cGAS-STING signaling pathway senses the presence of cytosolic DNA, induces strong type I interferon responses, and enhances inflammatory cytokine production, placing it as an important axis in infection, autoimmunity, and tumor immunity. Abstract. 12 While mouse models have been developed for IAV and SARS-CoV-2, there are species-specific differences in the lung in both infection dynamics and tissue-specific cell compositions between mouse and human. 1128/JVI. Antiviral research, 187, 105015-105015 (2021-01-15) May 28, 2021 · Because 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 A). TBK1, and its homologue Aug 5, 2021 · Humphries et al. 05040, StemCell Technologies), then seeded (3. For SARS-CoV-2 to enter cells, its surface glycoprotein spike (S) must be cleaved at two different sites by host cell protease Oct 2, 2020 · Antiviral strategies to inhibit Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) and the pathogenic consequences of COVID-19 are urgently required. 2 It decreases tumor volume and increases ACS infectious diseases 5 (5), 659-674, 2018. 104933) This article is published in Antiviral Research. , Yan Z. 2021;187:105015. Journal of Virology May 28, 2021 · On the basis of these findings, we next assessed whether diABZI-4 could also confer protection against RNA viruses. Antiviral Res 187: 105015 [Google Scholar] A synthetic STING agonist inhibits the replication of human parainfluenza virus 3 and rhinovirus 16 through distinct mechanisms. Long-acting muscarinic antagonists and β 2-agonists and inhaled corticosteroids inhibit the exacerbation of COPD and bronchial asthma caused by infection with viruses, including HCoV-229E. 2,3 Considering the critical role of STING in aberrant cytokine responses in the late phase of Oct 5, 2023 · Induction of antiviral gene expression by cyclosporine A, but not inhibition of cyclophilin A or B, contributes to its restriction of human coronavirus 229E infection in a lung epithelial cell line Antiviral Res. We find that the SARS-CoV-2 HRC-derived cholesterol conjugate potently inhibits fusion mediated by Dec 8, 2022 · The coronavirus disease 2019 (COVID-19) pandemic caused by the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has cast a notorious damage to the public health and global economy. Triggering of type I IFN production by the MDA5 sensor following infection by SARS-CoV-2 is dependent upon ISG15 conjugation. The ER stress inducer thapsigargin exerts potent antiviral effects, partially reverses the virus Mar 25, 2022 · Stimulator of interferon genes (STING) contributes to immune responses against tumors and may control viral infection including SARS-CoV-2 infection. For now, several STING agonists such as ADU Sep 27, 2024 · more, in primary human airway cultures, SARS-CoV-2-infected cells display markedly lower levels of STING expression, and pharmacolo- gical inhibition of STING enhances infectious virion release Jun 23, 2024 · We show that GA is a promising STING agonist that activates STING at an early stage (1. May 18, 2021 · Humphries et al. 01 Mar 2021 - Antiviral Research Qingyuan Zhu , Yaling Zhang , Li Wang , Xiangyu Yao , Daitze Wu , Junjun Cheng , Xiaoyu Pan , Haixia Liu , Zhipeng Yan , Lu Gao - Pharmacological activation of STING protects against SARS-CoV-2 infection. b Structure of SARS-CoV-2 6-HB is shown in cartoon representation with HR1 colored in green and HR2 in cyan. 2021. Read more Jul 23, 2020 · The novel emerged SARS-CoV-2 has rapidly spread around the world causing acute infection of the respiratory tract (COVID-19) that can result in severe disease and lethality. , Inhibition of coronavirus infection by a synthetic STING agonist in primary human airway system. Epithelial function influences inflammation in chronic respiratory diseases. Published on It inhibits the cytopathic effect of the common cold human coronavirus 229E (HCoV-229E) in infected MRC-5 cells (EC 50 = 3 nM). ANTIVIRAL. 1126/sciimmunol. By silico screening of drug libraries, several antagonists of cGAS have been developed from antimalarial drugs (AMDs), including hydroxychloroquine (HCQ), quinacrine (QC), and ACMA, . Inhibition of coronavirus infection by a synthetic STING agonist in primary human airway system. In this review, we detail the novel cellular sensors that are dependent on Oct 29, 2024 · Stimulator of interferon genes (STING) is an endoplasmic reticulum (ER) protein that plays a crucial role in cytosolic DNA-mediated innate immunity. STING agonists are recently being widely investigated and applied in cancer immunotherapy due to their capacity of triggering innate immunity in the local tissues and efficiently alleviate the immunosuppressive environment by triggering the cGAS (cyclic GMP-AMP synthase) -STING signaling pathway [, , , ]. doi: 10. 2023. To date, numerous efficacious vaccines have been developed and rolled out (5, 6). 55: Inhibition of coronavirus infection by a synthetic STING agonist in primary human airway system. Feb 8, 2021 · The stimulator of interferon genes (STING) is an endoplasmic reticulum transmembrane protein that is a target of therapeutics for infectious diseases and cancer. Jul 2, 2023 · Previously we identified a non-nucleotide tricyclic agonist BDW568 that activates human STING (stimulator of interferon genes) gene variant containing A230 in a human monocyte cell line (THP-1). 1 Antiviral response relies on pattern‐recognition receptors (PRRs) of the innate immune system which recognize pathogen‐associated molecular patterns (PAMPs). The antiviral RNA-dependent polymerase inhibitor remdesivir reduces length of hospitalization and deaths from COVID-19 (3). HRV is the most common cold-causing virus and it Dec 3, 2024 · Inhibition of coronavirus infection by a synthetic STING agonist in primary human airway system. (B) Screening of AS-circRNAs by virus titer assays identifies AS_1–75 as the most effective antiviral circRNA. L Wang, Dec 7, 2022 · 68. (A) WT and Sting –/– 3D4/21 cells were seeded in 12-well plates at a density of 1 × 10 5 per well. Immunol. We investigated the mechanism by which PLpro antagonizes cellular antiviral responses. In this study, we examined the impact of the STING signaling Aug 29, 2024 · A synthetic STING agonist inhibits the replication of human parainfluenza virus 3 and rhinovirus 16 through distinct mechanisms. 9B-D, respectively PASI scores at the site of injection. Aug 29, 2024 · In this study, a dose-dependent inhibitory effect of SR717 was observed against numerous strains of PRRSV using qRT-PCR, IFA, and WB methods. To develop specific anti-coronavirus therapeutics and prophylactics, the molecular mechanism that underlies viral infection must first be defined. As shown in Figure 1B, STING knockout cells exhibited increased susceptibility to coronavirus infection, as evidenced by the elevated expression levels Jun 25, 2024 · In this Review, the authors summarize the literature around immune cancer cell STING signaling and how it is finely balanced between pro-tumorigenic and anti-tumorigenic functions. org. 105015 [PMC free article] [Google Scholar] Background: Excessive inflammation triggered by a hitherto undescribed mechanism is a hallmark of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and is associated with enhanced pathogenicity and mortality. Antiviral Research 2021-03 of cellular furin content as a potential factor determining the susceptibility of cultured human and animal cells to coronavirus infectious bronchitis virus infection. SARS-CoV-2 is a member of the Coronaviridae family of viruses. Antiviral Res 187, 105015 (2021). Vero E6 cells were transfected with increasing quantities of circRNAs (25, 250 and 2500 ng per assay; light gray; as indicated Apr 15, 2024 · However, up to now, none of STING agonists have been approved for clinical use. 2 It decreases tumor volume and increases Dec 3, 2024 · Inhibition of coronavirus infection by a synthetic STING agonist in primary human airway system. RESULTS Jun 27, 2022 · human coronavirus HCoV-OC43 HRC domain, has been reported to display inhibition in a SARS-CoV-2 S-mediated cell-cell fusion assay and in a pseudotyped virus infection assay, and has been proposed as a pan-coronavirus inhibitor (21). Cortisol, a physiologic glucocorticoid (GC), is essential for growth and differentiation of the airway epithelium. 1016/j. Epub 2023 Oct 5. However, its broad-spectrum antiviral activity against other respiratory viruses in human airway epithelial cells, which are the primary targets of these infections, is not well established. Both STING agonists and antagonists have demonstrated their ability to enhance mouse survival against coronavirus, however, the physiological role of endogenous STING in coronavirus infection remains unclear. Inhibition of SARS-CoV-2 proliferation by AS-circRNAs: viral infection assays. Zhu Q, Zhang Y, Wang L, Yao X, Wu D, Cheng J, et al. Background. BALB/cJ female mice injected with diABZI on a shaved back were evaluated for erythema, scaling, and induration. STING A230 alleles, including HAQ and AQ, are less common STING variants in human population. Although infection initiates in the proximal airways, severe and sometimes fatal symptoms of the disease are caused by infection of the alveolar type A diamidobenzimidazole STING agonist protects against SARS-CoV-2 infection. 03. The recent outbreak of coronavirus disease (COVID-19) caused by SARS-CoV-2 infection in Wuhan, China has posed a serious threat to global public health. 1016 Inhibition of TANK binding kinase 1 by herpes simplex virus 1 facilitates productive infection. It activates interferon (IFN) and inflammatory cytokine responses to defend against infection by microorganisms. 105015. Several studies have demonstrated that STING is capable of inhibiting the proliferation of DNA viruses by mediating the production of cytokines, while being able to inhibit RNA virus proliferation [ 31 , 32 ]. As a major component of innate immunity and a positive regulator of interferons, the Stimulator of interferon gene (STING) has an immunotherapy potential to govern a variety of infectious diseases. 351) by transiently stimulating IFN signaling. The type I interferon (IFN) system is a rapidly mobilized line of defense against invading microbes that initiates and directs cellular and systemic processes to eliminate pathogenic threats. Q Zhu, Y Zhang, L Wang, X Yao, D Wu, J Cheng, X Pan, H Liu, Inhibitory effect of ginsenoside-Rd on carrageenan-induced inflammation in rats. Qingyuan Zhu, Yaling Zhang, Li Wang, Xiangyu Yao, It inhibits the cytopathic effect of the common cold human coronavirus 229E (HCoV-229E) in infected MRC-5 cells (EC 50 = 3 nM). Although these vaccines are protective against homologous Inhibition of coronavirus infection by a synthetic STING agonist in primary human airway system. The rapid global spread of SARS-CoV-2 highlights an urgent need to develop effective therapeutics for blocking SARS-CoV-2 infection and spread. J Virol, DOI: 10. Qingyuan Zhu; Yaling Zhang; Li Wang; Xiangyu Yao; Daitze Wu; Junjun Cheng; A synthetic STING agonist inhibits the replication of human parainfluenza virus 3 and rhinovirus 16 through distinct ACS Infectious Diseases. 105015 Corpus ID: 231578908; Inhibition of coronavirus infection by a synthetic STING agonist in primary human airway system @article{Zhu2021InhibitionOC, title={Inhibition of coronavirus infection by a synthetic STING agonist in primary human airway system}, author={Qingyuan Zhu and Yaling Zhang and Li Wang and Xiangyu Yao and Daitze Oct 29, 2024 · Stimulator of interferon genes (STING) is an endoplasmic reticulum (ER) protein that plays a crucial role in cytosolic DNA-mediated innate immunity. antiviral. Oct 20, 2020 · (C) Inhibition of fusion mediated by SARS-CoV-2 S mutants, MERS-CoV S, and SARS-CoV-1 S. However, early-phase clinical Sep 20, 2021 · Here, Shaban et al. Antiviral Res (2021) 187:105015. Antivir. The article was published on 2020-09-17 and is currently open access. Recent evidence has shown that the control of multiple immune functions, including chronic inflammation, pathogen responses, lymphocyte activation, and regulatory signaling, is altered by K63 ubiquitination. The Stimulator of Interferon Genes (STING) is a crucial element of the host antiviral pathway and plays a pivotal but complex role in the infection and Oct 23, 2020 · Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as the causative agent of coronavirus disease 2019, also known as COVID-19, is a beta-coronavirus which belongs to the family of Coronaviridae and is currently responsible for the third human coronavirus outbreak in the past 20 years, after SARS (now often referred to as SARS-CoV-1) in 2002/03 Nov 3, 2021 · We infected human lung epithelial cell line Calu-3 and HeLa cells expressing ACE2 (HeLa-ACE2) with SARS-CoV-2, and then examined the phosphorylation of STING at Ser366 (phospho-STING Ser366), a hallmark of STING activation. 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 ac Sep 20, 2020 · A synthetic STING agonist inhibits the replication of human parainfluenza virus 3 and rhinovirus 16 through distinct mechanisms. Mar 1, 2021 · Request PDF | Inhibition of coronavirus infection by a synthetic STING agonist in primary human airway system | The newly emerged severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2 Inhibition of coronavirus infection by a synthetic STING agonist in primary human airway system. 2 It decreases tumor volume and increases Sep 18, 2023 · Here, we initially observed that idronoxil (IDX), a synthetic flavonoid closely related to daidzein, stood out among other flavonoid compounds as a potent inhibitor of STING-induced IRF3 and NF-κB transcriptional programmes upon cGAS overexpression (in HEK-STING cells), or STING-induced signalling in both human and murine cell lines (mouse L929 cells, mouse Liu W et al. , Sci. 1. In this study, we examined the impact of the STING signaling Dec 4, 2023 · STING agonist, and a non-nucleotide-based synthetic STING agonist comprising two linked, symmetry-related amidobenzimi- dazole-based compounds (diABZI) selected for its enhanced Inhibition of coronavirus infection by a synthetic STING agonist in primary human airway system. , Liu H. IRF3 and NFκB drive the expression of inflammatory mediators, type I IFNs, and in Apr 13, 2023 · human STING to block infection of both HCoV-OC43 and SARS-CoV-2. A broad range of innate immune cells, including macrophages, neutrophils, dendritic cells, natural killer (NK) cells, eosinophils, basophils, and innate lymphoid cells (ILCs), are activated during SARS-CoV-2 infection and COVID-19 pathogenesis. The diamidobenzimidazole (diABZI), a STING agonist is internalized 1. 00490-00421 (2021). Oct 29, 2024 · Stimulator of interferon genes (STING) is an endoplasmic reticulum (ER) protein that plays a crucial role in cytosolic DNA-mediated innate immunity. The ones marked * may be different from the article in the profile. B, 1. In this study, we examined the impact of the STING signaling Article Title: A novel, anatomy-similar in vitro model of 3D airway epithelial for anti-coronavirus drug discovery Journal: bioRxiv doi: 10. 433824 SN-011 is a novel STING inhibitor that targets the cyclic dinucleotide binding pocket and shows good efficacy in vivo. INTRODUCTION. , Pan X. DISCOVERY OF STING. We measured the One of the potent STING agonists diABZI was then tested in subsequent studies due to its significant potency and higher bioavailability. May 18, 2021 · Inhibition of coronavirus infection by a synthetic STING agonist in primary human airway system. diABZI-4 inhibited SARS Mar 1, 2021 · We discovered that dimeric amidobenzimidazole (diABZI), a synthetic small molecule STING receptor agonist, showed potent anti-coronavirus activity against both the Aug 29, 2024 · In this work, we investigated the antiviral activity of the STING agonist diABZI-4 in immortalized human lung cells, primary human airway epithelial cells, and a C57BL/6J mouse model for IAV. An appropriate immune response is necessary to inhibit SARS-CoV-2 spread throughout the body. In addition, the steroid dexameth-asone has also been approved for use in severe COVID-19 (4). Recent advances have illuminated the mechanisms of STING activation and the meticulous regulation of this pathway to prevent excessive signaling (). 2020. The COVID-19 pandemic poses a serious global health threat. Dec 4, 2023 · STING inhibitor H-151 exerts great effects in relieving the immunopathology response and ameliorating the lung pathology at the late stage of SARS-CoV-2 infection Li et al. Qingyuan Zhu et al. To further characterize the mechanism of BDW568, we obtained the crystal May 1, 2021 · Europe PMC is an archive of life sciences journal literature. Moreover, both viral replication and lung Aug 31, 2022 · Both STING agonist alone and in combination with bortezomib increased concentrations of IFNβ and TNFα (Fig. In light of this we sought to identify small molecules capable Stimulation of STING leads to the recruitment and phosphorylation of the transcription factors IRF3 and NFκB through the kinases TBK1 and IKKε (Ishikawa & Barber, 2008; Ishikawa et al, 2009; Diner et al, 2013; Zhang et al, 2013; Ablasser et al, 2013a; Shang et al, 2019; Zhang et al, 2019). 26 At 8 h post infection, phospho-STING Ser366 was barely detected in Calu-3 and HeLa-ACE2 cells, while after infection for 16 Pattern recognition receptors (PRRs) are host cellular proteins that recognize pathogen associated molecular patterns, such as viral nucleic acids, capsids, bacterial peptidoglycans, lipopolysaccharides or other metabolites 1, and subsequently activate a proinflammatory cytokine response and cell death pathways 2–3. Dec 27, 2024 · Zhu Q, Zhang Y, Wang L, Yao X, Wu D, Cheng J, et al. Qingyuan Zhu, Yaling Zhang, Li Wang, Xiangyu Yao, Daitze Wu, The cGAS–STING pathway has a central role in the pathogenesis of severe COVID-19 by driving the increase in type I interferons that occurs in the later stages of SARS-CoV-2 Dec 7, 2022 · Inhibition of coronavirus infection by a synthetic STING agonist in primary human airway system. Virology It inhibits the cytopathic effect of the common cold human coronavirus 229E (HCoV-229E) in infected MRC-5 cells (EC 50 = 3 nM). by Qingyuan Zhu, Hui Hu, Haixia Liu, Hong Shen, Zhipeng Yan, Lu Gao. by Qingyuan Zhu, Yaling Zhang, Li Wang, Xiangyu Yao, Daitze Wu, Junjun Cheng, Xiaoyu Pan, Haixia Liu, Zhipeng Yan, Lu Gao. PubMed Abstract | CrossRef Full Text | Inhibition of coronavirus infection by a synthetic STING agonist in primary human airway system. Here, the authors show that a STING agonist nanoparticle, termed NanoSTING Mar 3, 2018 · INTRODUCTION. May 5, 2021 · INTRODUCTION. Res. The cGAS-STING pathway drives type I IFN immunopathology in COVID-19. However, the role of STING in the control of RNA virus infection remains Inhibition of coronavirus infection by a synthetic STING agonist in primary human airway system. Furthermore, SR717 was found to stimulate the production of anti-viral molecules and trigger the activation of the signaling cascade known as the stimulator of interferon genes (STING) pathway, which contributed to Sep 18, 2023 · TANK-binding kinase 1 (TBK1) is a key signalling component in the production of type-I interferons, which have essential antiviral activities, including against SARS-CoV-2. Interferons (IFNs) were first described in the 1950s as factors released during infection to interfere with viral growth (Issacs & Lindenmann, 1988; Vilcek, 2006). 1016/J. 2021; Mar 14, 2023 · In this study, we investigated the anti-coronavirus activity triggered by STING activation. c HR1 trimer of SARS-CoV-2 6-HB is shown in electrostatic surface, and HR2 domain is shown in cartoon representation, the Dec 1, 2023 · STING agonists are recently being widely investigated and applied in cancer immunotherapy due to their capacity of triggering innate immunity in the local tissues and efficiently alleviate the immunosuppressive environment by triggering the cGAS (cyclic GMP-AMP synthase) -STING signaling pathway [[1], [2], [3], [4]]. 2 The response is initiated by cytoplasmic 1 |. We focused on human coronavirus OC43 (HCoV-OC43) and SARS-CoV-2. 1101/2021. Wu D. The article focuses on the topics: Sting & Stimulator of interferon genes. L. DOI: 10. We discovered that dimeric amidobenzimidazole (diABZI), a synthetic small May 18, 2021 · 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 We found that diABZI was active against SARS-CoV-2 in primary human respiratory epithelial cells and in vivo in two different mouse models of infection. Antiviral research, 187, 105015-105015 (2021-01-15) 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. , cancers, dead cells, or damaged mitochondria), binds to and activates cyclic Jan 19, 2022 · The cGAS–STING pathway has a central role in the pathogenesis of severe COVID-19 by driving the increase in type I interferons that occurs in the later stages of SARS-CoV-2 infection. Dec 8, 2015 · This enabled identification of the STING protein as required for G10’s biological activity thus indicating that the compound is the first described human-specific synthetic small molecule STING agonist. bwvdwof ijkdxqw ahllcv plzcmi nqas amtqk raws zfd vvwfxz gdgjqqo