Inhibition of coronavirus infection by a synthetic STING agonist in primary human airway system

Zhu, Qingyuan; Zhang, Yaling; Wang, Li; Yao, Xiangyu; Wu, Daitze; Cheng, Junjun; Pan, Xiaoyu; Liu, Haixia; Yan, Zhipeng

doi:10.1016/j.antiviral.2021.105015

Cited by 37 publications

(40 citation statements)

References 37 publications

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“…2L-M). Two other studies have also shown diABZI molecules impair SARS-CoV-2 replication in lung epithelial cells (17,18) diABZI-4 protects against SARS-CoV-2 infection Given that diABZI-4 strongly inhibited SARS-CoV-2 replication in lung epithelial cells we next determined if diABZI-4 could also prevent SARS-CoV-2 infection in vivo. SARS-CoV-2 cannot bind to murine ACE2; thus, a SARS-CoV-2 infection cannot be established in conventional laboratory mouse strains (16,19).…”

Section: Diabzi-4 Inhibits Sars-cov-2 Replicationmentioning

confidence: 98%

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

et al. 2021

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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.

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Section: Diabzi-4 Inhibits Sars-cov-2 Replicationmentioning

confidence: 98%

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

et al. 2021

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“…Impaired autophagy contributes to the aberrant activation of STING signaling, thereby leading to uncontrolled inflammation and cell death in sepsis ( Hu et al, 2019 ). It has been demonstrated that STING agonists, such as diABZI, have potent antiviral activity against the respiratory RNA viruses human parainfluenza type 3 virus, rotavirus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, dependent on the IFN pathway ( Zhu et al, 2020 ; Zhu et al, 2021 ). Therapeutics such as chloroquine and its derivatives, which inhibit the autophagic pathway, have been suggested for treatment of COVID-19 ( Wang et al, 2020 ), suggesting these is a close connection between autophagy and cGAS–STING signaling in the fight against pathogens.…”

Section: Introductionmentioning

confidence: 99%

Crosstalk Between Autophagy and the cGAS–STING Signaling Pathway in Type I Interferon Production

Zhang

Wang

Gou

et al. 2021

Front. Cell Dev. Biol.

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Innate immunity is the front-line defense against infectious microorganisms, including viruses and bacteria. Type I interferons are pleiotropic cytokines that perform antiviral, antiproliferative, and immunomodulatory functions in cells. The cGAS–STING pathway, comprising the main DNA sensor cyclic guanosine monophosphate/adenosine monophosphate synthase (cGAS) and stimulator of IFN genes (STING), is a major pathway that mediates immune reactions and is involved in the strong induction of type I IFN production, which can fight against microbial infections. Autophagy is an evolutionarily conserved degradation process that is required to maintain host health and facilitate capture and elimination of invading pathogens by the immune system. Mounting evidence indicates that autophagy plays an important role in cGAS–STING signaling pathway-mediated type I IFN production. This review briefly summarizes the research progress on how autophagy regulates the cGAS–STING pathway, regulating type I IFN production, with a particular focus on the crosstalk between autophagy and cGAS–STING signaling during infection by pathogenic microorganisms.

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“…Separate groups of researchers have reached an agreement that direct activation of STING can robustly block SARS-CoV-2 infection. Moreover, they found that the STING agonist, diABZI and diABZI-4, can effectively restrict SARS-CoV-2 replication ( Chipurupalli et al, 2020 ; Zhu et al, 2021 ). Furthermore, Wu et al (2021) expanded the function of a novel STING agonist, CDG SF , as an adjuvant for the SARS-CoV-2 vaccine.…”

Section: Severe Acute Respiratory Syndrome Coronavirus-2 Infection and Cyclic Gmp-amp Synthase-stimulator Of Interferon Genesmentioning

confidence: 99%

The Regulatory Network of Cyclic GMP-AMP Synthase-Stimulator of Interferon Genes Pathway in Viral Evasion

et al. 2021

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Virus infection has been consistently threatening public health. The cyclic GMP-AMP synthase (cGAS)-Stimulator of Interferon Genes (STING) pathway is a critical defender to sense various pathogens and trigger innate immunity of mammalian cells. cGAS recognizes the pathogenic DNA in the cytosol and then synthesizes 2′3′-cyclic GMP-AMP (2′3′cGAMP). As the second messenger, cGAMP activates STING and induces the following cascade to produce type I interferon (IFN-I) to protect against infections. However, viruses have evolved numerous strategies to hinder the cGAS-STING signal transduction, promoting their immune evasion. Here we outline the current status of the viral evasion mechanism underlying the regulation of the cGAS-STING pathway, focusing on how post-transcriptional modifications, viral proteins, and non-coding RNAs involve innate immunity during viral infection, attempting to inspire new targets discovery and uncover potential clinical antiviral treatments.

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Inhibition of coronavirus infection by a synthetic STING agonist in primary human airway system

Cited by 37 publications

References 37 publications

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

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

Crosstalk Between Autophagy and the cGAS–STING Signaling Pathway in Type I Interferon Production

The Regulatory Network of Cyclic GMP-AMP Synthase-Stimulator of Interferon Genes Pathway in Viral Evasion

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