Small molecule activators of the cGAS-STING axis have the potential to augment immune response . STING's structure and its binding mechanism to cyclic dinucleotides were unknown. Nicotinamide adenine dinucleotide, abbreviated NAD +, is a coenzyme found in all living cells.The compound is a dinucleotide, since it consists of two nucleotides joined through their phosphate groups: with one nucleotide containing an adenine base, and the other containing nicotinamide.. b, Crystal structure of a STING receptor from the bacterium C. granulosa (CgSTING) in the apo state reveals an open configuration with a solvent exposed cyclic-dinucleotide-binding pocket at the . The production of cytokines by the immune system in response to cytosolic DNA plays an important role in host defense, autoimmune disease, and cancer immunogenicity. Cell Reports 8, 1668-1676. Association of cytosolic DNA with cyclic-GMP-AMP synthase (cGAS . In addition to infection, the pathophysiology of an ever-increasing number of sterile inflammatory conditions in humans involves the recognition of DNA through cGAS. cAMP modifies cell function in all eukaryotic cells, principally through the activation of cAMP-dependent protein kinase (PKA), but also through cAMP-gated ion channels and guanine nucleotide . In absence of cyclic nucleotide (c-di-GMP or cGAMP), the protein is autoinhibited by an intramolecular interaction between the cyclic dinucleotide-binding domain (CBD) and the C-terminal tail (CTT) (PubMed:22579474, PubMed:22705373, PubMed:22728658, PubMed:22728660, PubMed:22728659). To facilitate the development of compounds that target human STING, we combined structural, biophysical, and cellular assays to study mouse and human chimeric . STING agonists, related clinical trials and agonist delivery systems. Here we show that HIV infection activates cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) to produce cGAMP, which binds to and activates the adaptor protein STING to induce type I interferons and other cytokines. In 2013, Kim et al. STING is a member of the cGAS‐STING pathway and a receptor of cyclic dinucleotides (CDNs) that act as second messengers. The U.S. Department of Energy's Office of Scientific and Technical Information 12: e0185359; Molecular mechanisms and cellular functions of cGAS-STING signalling. Here we used . DOI: 10.1073/pnas.2105465118. Since the discovery of c-di-GMP as a second messenger for innate immune response mediated by STING, subsequent studies demonstrated Aberrant signaling of this pathway has been closely linked to multiple diseases . Upon binding to DNA, cGAS synthesises the cyclic dinucleotide 2′3′-cGAMP that binds to the adaptor protein STING and thereby triggers IRF3- and NFκB-dependent transcription. Here, in silico docking identified a potent STING antagonist SN-011 that binds with higher affinity to the cyclic dinucleotide (CDN)-binding pocket of STING than endogenous 2'3'-cGAMP. Their studies provide a useful approach to understand biological functions of 2′3′-cGAMP and its roles in immune-related diseases. Cell Reports 8, 1668-1676. At first, STING is known to play an important role in type I IFN-mediated innate immunity and anti-viral responses by sensing of DNA virus or self DNA [14,15].

STING inhibitors target the cyclic dinucleotide binding pocket. (canceled) 16. 2021 Jun 15;118 (24):e2105465118. Both variants display the same binding pocket, since the R71H mutation is part of the transmembrane domain, and . 2 SLC19A1 is a cyclic dinucleotide transporter 3 4 Rutger D. Luteijn1, . STING inhibitors target the cyclic dinucleotide binding pocket, Proceedings of the National . [22] This conformational change is transduced over the ER membrane and only in the closed conformation can STING recruit and activate protein kinases TBK1 and IKK. The polymers bind to a non-competitive STING surface site distinct from the conventional cyclic dinucleotide-binding pocket, and also induce condensation of STING proteins via polyvalent interactions. The ligand-binding pocket binds 2′3′-cyclic GMP-AMP (cGAMP), cyclic di-AMP (CDA), and cyclic di-GMP (CDG), the transmembrane region anchors STING onto the endoplasmic reticulum (ER) membrane and is required for STING signaling, and the linker region is the site of several disease-causing mutations in STING. 'Cold', nonimmunogenic tumors are less responsive to immune checkpoint inhibitors; therefore, promoting T cells infiltration in the tumor microenvironment is a promising approach . Cyclic dinucleotides (CDNs), such as bis-(3',5')-cyclic dimeric GMP and c-di-AMP [bis-(3',5')-cyclic dimeric AMP], are known to be produced by prokaryotes and to function as second messengers in motility, proliferation, and developmental processes (1 - 3).Recently, the enzyme, cyclic GMP-AMP (cGAMP) synthase, which synthesizes cGAMP after binding to cytosolic double-stranded DNA in . STING R232 variant (human recombinant) contains amino acids 138-379 with an arginine at position 232. 12A) was initially obtained as a low activity hit with an IC 50 value of 7300 nmol/L in the HAQ STING-cGAMP displacement assay. DNA is normally found in the nucleus of the cell. The cGMP-AMP synthase (cGAS)-STING-IRF3 pathway, a novel target for immunotherapy. The innate immune DNA sensor cGAS produces a noncanonical cyclic dinucleotide that activates human STING. WALTHAM, MA & MONTREAL, QC, November 3, 2021 - Ventus Therapeutics U.S., Inc., a biotechnology company . 25 In the resting state, STING protein exists as a . Upon binding to DNA, cGAS synthesises the cyclic dinucleotide 2′3′-cGAMP that binds to the adaptor protein STING and thereby triggers IRF3- and NFκB-dependent transcription. reported that 5,6-dimethylxanthenone-4-acetic acid (DMXAA) is a mouse STING agonist. Targeting STING with covalent small-molecule inhibitors.

Keywords: cGAS-STING pathway, Cancer biotherapy, Interferon, Cyclic dinucleotide, Agonist, Delivery system, Clinical trials Introduction Cancer biotherapy replies on stimulating the body 'santi-tumor biological response by initiating the host'sdefensive The binding of DNA to the cytosolic enzyme cGAMP synthase (cGAS), activates its enzymatic activity, leading to the synthesis of a second messenger, cyclic[G(2',5')pA(3',5')] (2'3'-cGAMP) 4-8. Binding of DNA activates the enzyme to produce a unique cyclic dinucleotide second messenger, cGAMP, which acts as an agonist for the STING (stimulator of interferon genes) receptor, leading to induction of a type I interferon response. Cyclic nucleotides are important second messengers involved in cellular events, and analogues of this type of molecules are promising drug candidates. PNAS, 2015, 112, 8947. For the discovery of natural ligands for STING, Burdette et al.

Structure-Function Analysis of STING Activation by c[G(2',5')pA(3',5')p] and Targeting by Anti-Viral DMXAA injection showed potent induction of inflammation, tumor necrosis, and, in some cases, durable tumor-specific adaptive immunity. Massachusetts, using in silico docking to identify small molecules that bind to the cyclic dinucleotide (CDN) binding pocket of STING. 1. We first confirmed that DMXAA induces IFN-β secretion in the mouse macro- How these charged CDNs pass through the lipid bilayer is unknown. Zillinger T, Wang W et al. Based on the large binding pocket of STING, Siu and co-workers 76 recently established a robust platform to identify STING inhibitors, and 1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl carboxylic acid (44, Fig. Cytosolic DNA activates cGAS (cytosolic DNA sensor cyclic AMP-GMP synthase)-STING (stimulator of interferon genes) signaling, which triggers interferon and inflammatory responses that help defend against microbial infection and cancer. In addition to c-di-GMP and c-di-AMP, it can . The cGMP-AMP synthase (cGAS)-STING-IRF3 pathway, a novel target for immunotherapy . 1-15.

In the mouse macrophage cell line Raw264.7 and L929 cells, DMXAA, similar to cyclic dinucleotide PAMPs and cyclic GMP-AMP, binds with m-STING to activate the TBK1-IRF3 pathway. Tumor infiltration by T cells has been shown to be a prerequisite for an efficient response to immunotherapeutic treatments [].]. STING plays a vital role in innate immune sensing of exogenous or endogenous DNA, which then induces type I interferons and other cytokines. STING inhibitors target the cyclic dinucleotide binding pocket Immunology and Inflammation. Piszczek G. Üren A. Brelidze T.I. 20,24 Human STING consists of 379 aa, including the 1-137 aa N-terminal transmembrane domain (NTD), 138-340 aa cyclic dinucleotide-binding domain (CBD), and 341-379 aa C-terminal tail (CTT). Cell Reports 3 , 1355-1361 (2013). cGAS is an exquisitely sensitive sensor for double-stranded DNA in the cytoplasm. STING is an ER protein composed of four transmembrane domains and a cytosolic domain formed by an alpha helix, a cyclic dinucleotide binding domain (CBD), and a C- terminal tail (CTT) carrying the binding sites for TBK1 and IRF3. Binding-pocket and lid-region substitutions render human STING sensitive to the species-specific : HY-100564 2',3'-cGAMP (2'-3'-cyclic GMP-AMP) is a endogenous cGAMP in mammalian cells. The molecule has an interesting macrocyclic structure, and behaves as a cyclic dinucleotide mimic with potent activity on all four human STING variants. Retroviruses, including HIV, can activate innate immune responses, but the host sensors for retroviruses are largely unknown. Binding of DNA activates the enzyme to produce a unique cyclic dinucleotide second messenger, cGAMP, which acts as an agonist for the STING (stimulator of interferon genes) receptor, leading to induction of a type I interferon response. STING inhibitors target the cyclic dinucleotide binding pocket [Immunology and Inflammation] Journal content | Jun 07, 2021 Recommendations: n/a Published in The cGAS-STING cytosolic DNA sensing pathway may play an integral role in the initiation of antitumor immune responses. Preclinical studies showed that ONM‑501 used in combination with a checkpoint inhibitor produces an immune response effective in treating . Through a kinase inhibitor library screen, we identified ALK inhibitors as the top inhibitors for STING activation in monocytes and macrophages. The allele A162 contains a unique point mutation (S162A) placed at the cyclic‑dinucleotide-binding site which confers sensitivity to DMXAA, a potent tumor vascular disrupting agent in mice [2]. Nature. The ARIAD/Takeda EGFR exon 20 insertion mutant (EGFRex20ins) inhibitor TAK-788 is a Breakthrough Therapy for patients with advanced non-small cell lung cancer (NSCLC) whose tumors harbor EGFR . Press Release Ventus Therapeutics to Present Data on Novel cGAS Small Molecule Inhibitors in the Modulation of Auto-Inflammation. Stimulator of interferon genes (STING), also known as transmembrane protein 173 (TMEM173), is a protein playing a major role in innate immunity. & MONTREAL--(BUSINESS WIRE)-- Ventus Therapeutics U.S., Inc., a biotechnology company that builds upon proprietary expertise in structural biology, protein science and its unique ReSOLVE platform to design small molecule therapies across a number of therapeutic areas, is presenting data for its cyclic GMP-AMP synthase (cGAS) inhibitor program this month at two upcoming . A STING-based fluorescent polarization assay for monitoring activities of cyclic dinucleotide metabolizing enzymes† Caroline W. Karanja,a Kofi S. Yeboah,a Wilson W. S. Onga and Herman O. Sintim *abc Cyclic dinucleoties, such as cGAMP, c-di-GMP and c-di-AMP, are fascinating second messengers with In addition to c-di-GMP and c-di-AMP, it can . STING inhibitors target the cyclic dinucleotide binding pocket Ze Honga,1 , Jiahao Meia,1 , Chenhui Lia,1, Guohui Baib, Munire Maimaitia , Haiyang Hua, Wenying Yuc, Li Sund, Lele Zhange , Dan Chenga, Yixian Liaoc, Senlin Lie, Yanping Youd, Hongbin Sunc, Jing Huangb , Xing Liuf , Judy Liebermang,2 , and Chen Wanga,2 aState Key Laboratory of Natural Medicines, Department of Life Science and . Presentations at the 4 th Inflammatory Skin Disease Summit and the American College of Rheumatology Annual Meeting describe newly identified cGAS inhibitors . Activation of this signaling pathway, via cytosolic sensing of bacterial-derived c-di-GMP/c-di-AMP or host-derived cGAMP, leads to the production of inflammatory interferons and cytokines that help resolve infection. Localization of DNA to the cytosol is associated with tumorigenesis, viral infection, and .

Hou et al.
June 22, 2021. STING. 21-23 It transduces signal from the cytosolic dsDNA sensor cGAS (cyclic GMP‐AMP synthase) to the transcription factor IRF3 (interferon regulatory factor 3) through the kinase TBK1 (TANK‐binding kinase 1) and to the . DMXAA was later discovered to activate mouse, but not human, STING, an adaptor protein in the cyclic dinucleotide cGAMP-mediated signaling pathway, inducing type I interferon expression. It activates interferon (IFN) and inflammatory cytokine responses to defend against infection by .

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.
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