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MEI Jiahao, HONG Ze, WANG Chen. Advances of drugs in targeting cGAS-STING signaling pathway[J]. Journal of China Pharmaceutical University, 2020, 51(3): 249-259. DOI: 10.11665/j.issn.1000-5048.20200301
Citation: MEI Jiahao, HONG Ze, WANG Chen. Advances of drugs in targeting cGAS-STING signaling pathway[J]. Journal of China Pharmaceutical University, 2020, 51(3): 249-259. DOI: 10.11665/j.issn.1000-5048.20200301

Advances of drugs in targeting cGAS-STING signaling pathway

Funds: This study was supported by the National Natural Science Foundation of China (No. 81672029)
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  • Received Date: November 23, 2019
  • Revised Date: April 20, 2020
  • Invasion of pathogenic microorganisms and cell damage lead to abnormal accumulation of DNA in the cytoplasm. Cyclic GMP-AMP synthase (cGAS) catalyzes the generation of second messenger 2", 3"-cGAMP by recognizing DNA in the cytoplasm, transmitting signals to downstream stimulators of interferon gene (STING). STING induces the translocation of transcription factors IRF3 and NF-κB into the nucleus to express and secrete inflammatory factors such as type I interferon, which activate the body"s innate and adaptive immune responses. Many studies have indicated that disturbance of cGAS-STING pathway regulation leads to the occurrence and development of various diseases such as microbial infection, tumor and autoimmune diseases. Therefore, the development of drugs targeting cGAS and STING proteins is of great clinical value. This paper reviews the latest research progress of cGAS-STING pathway and its roles in different diseases, and summarizes the small-molecule compounds that have been reported to regulate cGAS and STING, in order to provide theoretical reference for future cGAS-STING pathway-related drug discovery.
  • [1]
    . Annu Rev Immunol, 2014, 32(1): 461-488.
    [2]
    Ablasser A, Chen ZJ. cGAS in action: expanding roles in immunity and inflammation[J]. Science, 2019, 363(6431): eaat8657.
    [3]
    Civril F, Deimling T, De CC, et al. Structural mechanism of cytosolic DNA sensing by cGAS[J]. Nature, 2013, 498(7454): 332-337.
    [4]
    Zhang X, Wu J, Du F, et al. The cytosolic DNA sensor cGAS forms an oligomeric complex with DNA and undergoes switch-like conformational changes in the activation loop[J]. Cell Rep, 2014, 6(3): 421-430.
    [5]
    Andreeva L, Hiller B, Kostrewa D, et al. cGAS senses long and HMGB/TFAM-bound U-turn DNA by forming protein-DNA ladders[J]. Nature, 2017, 549(7672): 394-398.
    [6]
    Ablasser A, Goldeck M, Cavlar T, et al. cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING[J]. Nature, 2013, 498(7454): 380–384.
    [7]
    Shang G, Zhu D, Li N, et al. Crystal structures of STING protein reveal basis for recognition of cyclic di-GMP[J]. Nat Struct Mol Biol, 2012, 19(7): 725-727.
    [8]
    Zhao B, Du F, Xu P, et al. A conserved PLPLRT/SD motif of STING mediates the recruitment and activation of TBK1[J]. Nature, 2019, 569(7758): 718-722.
    [9]
    Zhao B, Shu C, Gao X, et al. Structural basis for concerted recruitment and activation of IRF-3 by innate immune adaptor proteins[J]. Proc Natl Acad Sci, 2016, 113(24): E3403-E3412.
    [10]
    Burdette DL, Monroe KM, Sotelo TK, et al. STING is a direct innate immune sensor of cyclic di-GMP[J]. Nature, 2011, 478(7370): 515-518.
    [11]
    Su J, Rui Y, Lou M, et al. HIV-2/SIV Vpx targets a novel functional domain of STING to selectively inhibit cGAS-STING-mediated NF-κB signalling[J]. Nat Microbiol, 2019, 4(12): 2552-2564.
    [12]
    Aguirre S, Luthra P, Sanchez MT, et al. Dengue virus NS2B protein targets cGAS for degradation and prevents mitochondrial DNA sensing during infection[J]. Nat Microbiol, 2017, 2(5): 17037.
    [13]
    Woo SR, Fuertes MB, Corrales L, et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors[J]. Immunity, 2014, 41(5): 830-842.
    [14]
    Konno H, Yamauchi S, Berglund A, et al. Suppression of STING signaling through epigenetic silencing and missense mutation impedes DNA damage mediated cytokine production[J]. Oncogene, 2018, 37(15): 2037–2051.
    [15]
    Wu S, Zhang Q, Zhang F, et al. HER2 recruits AKT1 to disrupt STING signalling and suppress antiviral defence and antitumour immunity[J]. Nat Cell Biol, 2019, 21(8): 1027-1040.
    [16]
    Elinav E, Nowarski R, Thaiss CA, et al. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms[J]. Nat Rev Cancer, 2013, 13(11): 759-771.
    [17]
    Ahn J, Xia T, Konno H, et al. Inflammation-driven carcinogenesis is mediated through STING[J]. Nat Commun, 2014, 5(1): 5166.
    [18]
    Chen Q, Boire A, Jin X, et al. Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer[J]. Nature, 2016, 533(7604): 493-498.
    [19]
    Gao D, Li T, Li XD, et al. Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases[J]. Proc Natl Acad Sci, 2015, 112(42): E5699-E5705.
    [20]
    Crow YJ, Chase DS, Lowenstein SJ, et al. Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1[J]. Am J Med Genet Part A, 2015, 167(2): 296-312.
    [21]
    Coquel F, Silva MJ, Técher H, et al. SAMHD1 acts at stalled replication forks to prevent interferon induction[J]. Nature, 2018, 557(7703): 57-61.
    [22]
    Crow YJ, Manel N. Aicardi–Goutières syndrome and the type I interferonopathies[J]. Nat Rev Immunol, 2015, 15(7): 429-440.
    [23]
    Liu Y, Jesus AA, Marrero B, et al. Activated STING in a vascular and pulmonary syndrome[J]. N Engl J Med, 2014, 371(6): 507-518.
    [24]
    Zhao Q, Wei Y, Pandol SJ, et al. STING signaling promotes inflammation in experimental acute pancreatitis[J]. Gastroenterology, 2018, 154(6): 1822-1835.
    [25]
    Rodero MP, Tesser A, Bartok E, et al. Type I interferon-mediated autoinflammation due to DNase II deficiency[J]. Nat Commun, 2017, 8(1): 2176.
    [26]
    Sliter DA, Martinez J, Hao L, et al. Parkin and PINK1 mitigate STING-induced inflammation[J]. Nature, 2018, 561(7722): 258-262.
    [27]
    Bakhoum SF, Ngo B, Laughney AM, et al. Chromosomal instability drives metastasis through a cytosolic DNA response[J]. Nature, 2018, 553(7689): 467-472.
    [28]
    An J, Durcan L, Karr RM, et al. Expression of cyclic GMP‐AMP synthase in patients with systemic lupus erythematosus[J]. Arthritis Rheumatol, 2017, 69(4): 800-807.
    [29]
    Ahn J, Gutman D, Saijo S, et al. STING manifests self DNA-dependent inflammatory disease[J]. Proc Natl Acad Sci, 2012, 109(47): 19386-19391.
    [30]
    Kerur N, Fukuda S, Banerjee D, et al. cGAS drives noncanonical-inflammasome activation in age-related macular degeneration[J]. Nat Med, 2018, 24(1): 50–61.
    [31]
    Petrasek J, Iracheta VA, Csak T, et al. STING-IRF3 pathway links endoplasmic reticulum stress with hepatocyte apoptosis in early alcoholic liver disease[J]. Proc Natl Acad Sci, 2013, 110(41): 16544–16549.
    [32]
    Iracheta VA, Petrasek J, Gyongyosi B, et al. Endoplasmic reticulum stress-induced hepatocellular death pathways mediate liver injury and fibrosis via stimulator of interferon genes[J]. J Biol Chem, 2016, 291(52): 26794–26805.
    [33]
    King KR, Aguirre AD, Ye YX, et al. IRF3 and type I interferons fuel a fatal response to myocardial infarction[J]. Nat Med, 2017, 23(12): 1481–1487.
    [34]
    Yu Y, Liu Y, An W, et al. STING-mediated inflammation in Kupffer cells contributes to progression of nonalcoholic steatohepatitis[J]. J. Clin Invest, 2018, 129(2): 546–555.
    [35]
    Zeng L, Kang R, Zhu S, et al. ALK is a therapeutic target for lethal sepsis[J]. Sci Transl Med, 2017, 9(412): eaan5689.
    [36]
    Marichal T, Ohata K, Bedoret D, et al. DNA released from dying host cells mediates aluminum adjuvant activity[J]. Nat Med, 2011, 17(8): 996–1002.
    [37]
    Carroll EC, Jin L, Mori A, et al. The vaccine adjuvant chitosan promotes cellular immunity via DNA sensor cGAS-STING-dependent induction of type I interferons[J]. Immunity, 2016, 44(3): 597-608.
    [38]
    Wang C, Guan Y, Lv M, et al. Manganese increases the sensitivity of the cGAS-STING Pathway for double-stranded DNA and is required for the host defense against DNA viruses[J]. Immunity, 2018, 48(4): 675-687.
    [39]
    Vincent J, Adura C, Gao P, et al. Small molecule inhibition of cGAS reduces interferon expression in primary macrophages from autoimmune mice[J]. Nat Commun, 2017, 8(1): 1-12.
    [40]
    Lama L, Adura C, Xie W, et al. Development of human cGAS-specific small-molecule inhibitors for repression of dsDNA-triggered interferon expression[J]. Nat Commun, 2019, 10(1): 2261.
    [41]
    Hall J, Brault A, Vincent F, et al. Discovery of PF-06928215 as a high affinity inhibitor of cGAS enabled by a novel fluorescence polarization assay[J]. PLoS One, 2017, 12(9): e0184843.
    [42]
    An J, Woodward JJ, Sasaki T, et al. Cutting Edge: Antimalarial drugs inhibit IFN-β production through blockade of cyclic GMP-AMP synthase-DNA interaction[J]. J Immunol, 2015, 194(9): 4089-4093.
    [43]
    An J, Woodward JJ, Lai W, et al. Inhibition of cyclic GMP-AMP synthase using a novel antimalarial drug derivative in Trex1-deficient mice[J]. Arthritis Rheumatol, 2018, 70(11): 1807-1819.
    [44]
    Liu ZS, Cai H, Xue W, et al. G3BP1 promotes DNA binding and activation of cGAS[J]. Nat Immunol, 2019, 20(1): 18-28.
    [45]
    Dai J, Huang YJ, He X, et al. Acetylation blocks cGAS activity and inhibits self-DNA-induced autoimmunity[J]. Cell, 2019, 176(6): 1447-1460.
    [46]
    Zhang X, Shi H, Wu J, et al. Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING[J]. Mol Cell, 2013, 51(2): 226-235.
    [47]
    Nakamura T, Miyabe H, Hyodo M, et al. Liposomes loaded with a STING pathway ligand, cyclic di-GMP, enhance cancer immunotherapy against metastatic melanoma[J]. J Control Release, 2015, 216: 149-157.
    [48]
    Smith TT, Moffett HF, Stephan SB, et al. Biopolymers codelivering engineered T cells and STING agonists can eliminate heterogeneous tumors[J]. J Clin Invest, 2017, 127(6): 2176-2191.
    [49]
    Ji LY, Hao J, Wang GC, et al. Recent research advances in STING agonists for cancer immunotherapy [J]. J China Pharm Univ(中国药科大学学报), 2020, 51(1): 1-9.
    [50]
    Banerjee M, Middya S, Basu S, et al. Abstract B43: novel small-molecule human STING agonists generate robust type I interferon responses in tumors[C]. Tumor Microenvironment: American Association for Cancer Research, 2018: B43-B43.
    [51]
    Ramanjulu JM, Pesiridis GS, Yang J, et al. Design of amidobenzimidazole STING receptor agonists with systemic activity[J]. Nature, 2018, 564(7736): 439-443.
    [52]
    Cheng N, Watkins SR, Junkins RD, et al. A nanoparticle-incorporated STING activator enhances antitumor immunity in PD-L1–insensitive models of triple-negative breast cancer[J]. JCI Insight, 2018, 3(22): e120638.
    [53]
    Siu T, Altman MD, Baltus GA, et al. Discovery of a novel cGAMP competitive ligand of the inactive form of STING[J]. ACS Med Chem Lett, 2019, 10(1): 92-97.
    [54]
    Li S, Hong Z, Wang Z, et al. The cyclopeptide Astin C specifically inhibits the innate immune CDN sensor STING[J]. Cell Rep, 2018, 25(12): 3405-3421.
    [55]
    Mukai K, Konno H, Akiba T, et al. Activation of STING requires palmitoylation at the Golgi[J]. Nat Commun, 2016, 7(1): 11932.
    [56]
    Hansen L, Buchan GJ, Rühl M, et al. Nitro-fatty acids are formed in response to virus infection and are potent inhibitors of STING palmitoylation and signaling[J]. Proc Natl Acad Sci, 2018, 115(33): E7768-E7775.
    [57]
    Haag SM, Gulen MF, Reymond L, et al. Targeting STING with covalent small-molecule inhibitors[J]. Nature, 2018, 559(7713): 269-273.
    [58]
    Gulen MF, Koch U, Haag SM, et al. Signalling strength determines proapoptotic functions of STING[J]. Nat Commun, 2017, 8(1): 427.
    [59]
    Liu H, ZhangH, Wu X, et al. Nuclear cGAS suppresses DNA repair and promotes tumorigenesis[J]. Nature, 2018, 563(7729): 131-136.
    [60]
    Tang CH, Zundell JA, Ranatunga S, et al. Agonist-mediated activation of STING induces apoptosis in malignant B cells[J]. Cancer Res, 2016, 76(8): 2137-2152.
    [61]
    Yu YH, Xu ZM, Zeng H, et al. Advances in the study of relationship between Caspases and innate immunity [J]. J China Pharm Univ(中国药科大学学报), 2019, 50(5): 622-630.
    [62]
    Yang RC, Duan FP, Chao JH, et al. Advances of microRNA activity in innate immunity [J]. J China Pharm Univ(中国药科大学学报), 2017, 48(4): 396-406.
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