Interrupting cyclic dinucleotide-cGAS–STING axis with small molecules

Sintim, Herman O.; Mikek, Clinton G.; Wang, Wanhe; Sooreshjani, Moloud Aflaki

doi:10.1039/c8md00555a

Cited by 22 publications

(15 citation statements)

References 126 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, acute tissue damage, as seen in the context of myocardial infarction, has been shown to involve cGAS-STING activation with adverse outcomes 203 . Based on these considerations, efforts are being undertaken to develop compounds that antagonize the cGAS-STING signalling cascade at various levels: DNA binding of cGAS, catalytic activity of cGAS, cGAMP binding to STING and the use of allosteric modulators of STING, such as inhibitors of palmitoylation 204 . Cyclic GMP-AMP synthase (cGAS) consists of a two-lobed catalytic domain and an extended amino-terminal (N-terminal) domain.…”

Section: Box 2 -Cgas-sting Signalling In Disease and Therapymentioning

confidence: 99%

Molecular mechanisms and cellular functions of cGAS–STING signalling

Hopfner

Hornung

2020

Nat Rev Mol Cell Biol

1,166

824

View full text Add to dashboard Cite

The cGAS-STING signalling axis, comprising the synthase for the second messenger cyclic GMP-AMP (cGAS) and the cyclic GMP-AMP receptor stimulator of interferon genes (STING), detects pathogenic DNA to trigger an innate immune reaction involving a strong type I interferon response against microbial infections. Notably however, besides sensing microbial DNA, the DNA sensor cGAS can also be activated by endogenous DNA, including extranuclear chromatin resulting from genotoxic stress and DNA released from mitochondria, placing cGAS-STING as an important axis in autoimmunity, sterile inflammatory responses and cellular senescence. Initial models assumed that co-localization of cGAS and DNA in the cytosol defines the specificity of the pathway for non-self, but recent work revealed that cGAS is also present in the nucleus and at the plasma membrane, and such subcellular compartmentalization was linked to signalling specificity of cGAS. Further confounding the simple view of cGAS-STING signalling as a response mechanism to infectious agents, both cGAS and STING were shown to have additional functions, independent of interferon response. These involve non-catalytic roles of cGAS in regulating DNA repair and signalling via STING to NF-κB and MAPK as well as STING-mediated induction of autophagy and lysosomedependent cell death. We have also learnt that cGAS dimers can multimerize and undergo liquid-liquid phase separation to form biomolecular condensates that could importantly regulate cGAS activation. Here, we review the molecular mechanisms and cellular functions underlying cGAS-STING activation and signalling, particularly highlighting the newly emerging diversity of this signalling pathway and discussing how the specificity towards normal, damage-induced and infection-associated DNA could be achieved.

show abstract

Section: Box 2 -Cgas-sting Signalling In Disease and Therapymentioning

confidence: 99%

Molecular mechanisms and cellular functions of cGAS–STING signalling

Hopfner

Hornung

2020

Nat Rev Mol Cell Biol

1,166

824

View full text Add to dashboard Cite

show abstract

“…HSV-2 has evolved multiple strategies to counteract this pathway, inhibiting IFN β production and evading host immunity [ 21 ]. Mangostin is a STING-targeted pathway agonist [ 22 ]. The binding activity of all the three was superior to that of mangostin, with geraniin showing the strongest binding activity (−11.71 kcal/mol), as shown in Table 2 .…”

Section: Resultsmentioning

confidence: 99%

Network Pharmacology-Based Systematic Analysis of Molecular Mechanisms of Geranium wilfordii Maxim for HSV-2 Infection

Zhang

Gao

Chen

et al. 2021

Evidence-Based Complementary and Alternative Medicine

View full text Add to dashboard Cite

Background. Being a traditional Chinese medicine, Geranium wilfordii Maxim (GWM) is used for the treatment of various infectious diseases, and its main active ingredients are the polyphenolic substances such as polyphenols quercetin, corilagin, and geraniin. Previous studies have demonstrated the anti-HSV-1 viral activity of these three main ingredients. Through employing a network pharmacological method, the authors of the present research intend to probe the mechanism of GWM for the therapeutic treatment of HSV-2 infection. Methods. The bioactive substances and related targets of GWM were obtained from the TCMSP database. Gene expression discrepancy for HSV-2 infection was obtained from dataset GSE18527. Crossover genes between disease target genes and GWM target genes were gained via Circos package. Distinctively displayed genes (DDGs) during HSV-2 infection were uploaded to the Metascape database with GWM target genes for further analysis. The tissue-specific distribution of the genes was obtained by uploading the genes to the PaGenBase database. Ingredient-gene-pathway (IGP) networks were constructed using Cytoscape software. Molecular docking investigations were carried out utilizing AutoDock Vina software. Results. Nine actively involved components were retrieved from the TCMSP database. After taking the intersection among 153 drug target genes and 83 DDGs, 7 crossover genes were screened. Gene enrichment analysis showed that GWM treatment of HSV-2 infection mainly involves cytokine signaling in the immune system, response to virus, epithelial cell differentiation, and type II interferon signaling (IFNG). One hub, three core objectives, and two critical paths were filtered out from the built network. Geraniin showed strong binding activity with HSV-2 gD protein and STING protein in molecular docking. Conclusions. This network pharmacological study provides a fundamental molecular mechanistic exploration of GWM for the treatment of HSV-2 infection.

show abstract

“…Studies on STING agonists focus on the optimization of cyclic dinucleotide (CDN) analogs and the screening of novel small molecule agonists. [110][111][112][113] CDNs, effective STING activators, are second messengers common in the immune systems of prokaryotes and eukaryotes. [114][115][116] There are two sources of CDNs: the cGAS pathway, which produces the atypical dinucleotide 2ʹ,3ʹ-cGAMP after the detection of cytoplasmic DNA; the other is found in the cytoplasm owing to the presence of pathogens.…”

Section: Agonists Of Stingmentioning

confidence: 99%

“…[114][115][116] There are two sources of CDNs: the cGAS pathway, which produces the atypical dinucleotide 2ʹ,3ʹ-cGAMP after the detection of cytoplasmic DNA; the other is found in the cytoplasm owing to the presence of pathogens. 112,[117][118][119] Numerous studies found that CDNs have strong antitumor effects and application prospects in the treatment of melanoma, colon cancer, and oral cancer. 39,[120][121][122] However, there are limitations in the use of CDNs as candidate drugs.…”

Section: Agonists Of Stingmentioning

confidence: 99%