Статті в журналах: "Cyclic dinucleotides"

1

Foley, J. F. "Cyclic Dinucleotides Get Stung." Science Signaling 4, no. 197 (November 1, 2011): ec303-ec303. http://dx.doi.org/10.1126/scisignal.4197ec303.

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2

Luteijn, Rutger D., Shivam A. Zaver, Benjamin G. Gowen, Stacia K. Wyman, Nick E. Garelis, Liberty Onia, Sarah M. McWhirter, et al. "SLC19A1 transports immunoreactive cyclic dinucleotides." Nature 573, no. 7774 (September 11, 2019): 434–38. http://dx.doi.org/10.1038/s41586-019-1553-0.

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3

Guey, Baptiste, and Andrea Ablasser. "A carrier for cyclic dinucleotides." Nature Immunology 20, no. 11 (October 10, 2019): 1418–20. http://dx.doi.org/10.1038/s41590-019-0521-z.

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4

Maelfait, Jonathan, and Jan Rehwinkel. "RECONsidering Sensing of Cyclic Dinucleotides." Immunity 46, no. 3 (March 2017): 337–39. http://dx.doi.org/10.1016/j.immuni.2017.03.005.

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5

Tschowri, Natalia. "Cyclic Dinucleotide-Controlled Regulatory Pathways in Streptomyces Species." Journal of Bacteriology 198, no. 1 (July 27, 2015): 47–54. http://dx.doi.org/10.1128/jb.00423-15.

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The cyclic dinucleotides cyclic 3′,5′-diguanylate (c-di-GMP) and cyclic 3′,5′-diadenylate (c-di-AMP) have emerged as key components of bacterial signal transduction networks. These closely related second messengers follow the classical general principles of nucleotide signaling by integrating diverse signals into regulatory pathways that control cellular responses to changing environments. They impact distinct cellular processes, with c-di-GMP having an established role in promoting bacterial adhesion and inhibiting motility and c-di-AMP being involved in cell wall metabolism, potassium homeostasis, and DNA repair. The involvement of c-dinucleotides in the physiology of the filamentous, nonmotile streptomycetes remained obscure until recent discoveries showed that c-di-GMP controls the activity of the developmental master regulator BldD and that c-di-AMP determines the level of the resuscitation-promoting factor A(RpfA) cell wall-remodelling enzyme. Here, I summarize our current knowledge of c-dinucleotide signaling inStreptomycesspecies and highlight the important roles of c-di-GMP and c-di-AMP in the biology of these antibiotic-producing, multicellular bacteria.

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6

Tosolini, Marie, Frédéric Pont, Delphine Bétous, Emmanuel Ravet, Laetitia Ligat, Frédéric Lopez, Mary Poupot та ін. "Human Monocyte Recognition of Adenosine-Based Cyclic Dinucleotides Unveils the A2a GαsProtein-Coupled Receptor Tonic Inhibition of Mitochondrially Induced Cell Death". Molecular and Cellular Biology 35, № 2 (10 листопада 2014): 479–95. http://dx.doi.org/10.1128/mcb.01204-14.

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Cyclic dinucleotides are important messengers for bacteria and protozoa and are well-characterized immunity alarmins for infected mammalian cells through intracellular binding to STING receptors. We sought to investigate their unknown extracellular effects by adding cyclic dinucleotides to the culture medium of freshly isolated human blood cellsin vitro. Here we report that adenosine-containing cyclic dinucleotides induce the selective apoptosis of monocytes through a novel apoptotic pathway. We demonstrate that these compounds are inverse agonist ligands of A2a, a Gαs-coupled adenosine receptor selectively expressed by monocytes. Inhibition of monocyte A2a by these ligands induces apoptosis through a mechanism independent of that of the STING receptors. The blockade of basal (adenosine-free) signaling from A2a inhibits protein kinase A (PKA) activity, thereby recruiting cytosolic p53, which opens the mitochondrial permeability transition pore and impairs mitochondrial respiration, resulting in apoptosis. A2a antagonists and inverse agonist ligands induce apoptosis of human monocytes, while A2a agonists are antiapoptotic.In vivo, we used a mock developing human hematopoietic system through NSG mice transplanted with human CD34+cells. Treatment with cyclic di-AMP selectively depleted A2a-expressing monocytes and their precursors via apoptosis. Thus, monocyte recognition of cyclic dinucleotides unravels a novel proapoptotic pathway: the A2a Gαsprotein-coupled receptor (GPCR)-driven tonic inhibitory signaling of mitochondrion-induced cell death.

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7

López-Villamizar, Iralis, Alicia Cabezas, Rosa María Pinto, José Canales, João Meireles Ribeiro, Joaquim Rui Rodrigues, María Jesús Costas, and José Carlos Cameselle. "Molecular Dissection of Escherichia coli CpdB: Roles of the N Domain in Catalysis and Phosphate Inhibition, and of the C Domain in Substrate Specificity and Adenosine Inhibition." International Journal of Molecular Sciences 22, no. 4 (February 17, 2021): 1977. http://dx.doi.org/10.3390/ijms22041977.

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CpdB is a 3′-nucleotidase/2′3′-cyclic nucleotide phosphodiesterase, active also with reasonable efficiency on cyclic dinucleotides like c-di-AMP (3′,5′-cyclic diadenosine monophosphate) and c-di-GMP (3′,5′-cyclic diadenosine monophosphate). These are regulators of bacterial physiology, but are also pathogen-associated molecular patterns recognized by STING to induce IFN-β response in infected hosts. The cpdB gene of Gram-negative and its homologs of gram-positive bacteria are virulence factors. Their protein products are extracytoplasmic enzymes (either periplasmic or cell–wall anchored) and can hydrolyze extracellular cyclic dinucleotides, thus reducing the innate immune responses of infected hosts. This makes CpdB(-like) enzymes potential targets for novel therapeutic strategies in infectious diseases, bringing about the necessity to gain insight into the molecular bases of their catalytic behavior. We have dissected the two-domain structure of Escherichia coli CpdB to study the role of its N-terminal and C-terminal domains (CpdB_Ndom and CpdB_Cdom). The specificity, kinetics and inhibitor sensitivity of point mutants of CpdB, and truncated proteins CpdB_Ndom and CpdB_Cdom were investigated. CpdB_Ndom contains the catalytic site, is inhibited by phosphate but not by adenosine, while CpdB_Cdom is inactive but contains a substrate-binding site that determines substrate specificity and adenosine inhibition of CpdB. Among CpdB substrates, 3′-AMP, cyclic dinucleotides and linear dinucleotides are strongly dependent on the CpdB_Cdom binding site for activity, as the isolated CpdB_Ndom showed much-diminished activity on them. In contrast, 2′,3′-cyclic mononucleotides and bis-4-nitrophenylphosphate were actively hydrolyzed by CpdB_Ndom, indicating that they are rather independent of the CpdB_Cdom binding site.

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8

Luteijn, Rutger D., Shivam A. Zaver, Benjamin G. Gowen, Stacia K. Wyman, Nick E. Garelis, Liberty Onia, Sarah M. McWhirter, et al. "Author Correction: SLC19A1 transports immunoreactive cyclic dinucleotides." Nature 579, no. 7800 (March 2020): E12. http://dx.doi.org/10.1038/s41586-020-2064-8.

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9

Danilchanka, Olga, and John J. Mekalanos. "Cyclic Dinucleotides and the Innate Immune Response." Cell 154, no. 5 (August 2013): 962–70. http://dx.doi.org/10.1016/j.cell.2013.08.014.

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10

Gutten, Ondrej, Petr Jurečka, Zahra Aliakbar Tehrani, Miloš Buděšínský, Jan Řezáč, and Lubomír Rulíšek. "Conformational energies and equilibria of cyclic dinucleotides in vacuo and in solution: computational chemistry vs. NMR experiments." Physical Chemistry Chemical Physics 23, no. 12 (2021): 7280–94. http://dx.doi.org/10.1039/d0cp05993e.

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11

Zhou, Jie, Yue Zheng, Benjamin T. Roembke, Sarah M. Robinson, Clement Opoku-Temeng, David A. Sayre, and Herman O. Sintim. "Fluorescent analogs of cyclic and linear dinucleotides as phosphodiesterase and oligoribonuclease activity probes." RSC Advances 7, no. 9 (2017): 5421–26. http://dx.doi.org/10.1039/c6ra25394f.

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12

Elmanfi, Samira, Herman O. Sintim, Jie Zhou, Mervi Gürsoy, Eija Könönen, and Ulvi K. Gürsoy. "Activation of Gingival Fibroblasts by Bacterial Cyclic Dinucleotides and Lipopolysaccharide." Pathogens 9, no. 10 (September 26, 2020): 792. http://dx.doi.org/10.3390/pathogens9100792.

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Human gingival fibroblasts (HGFs) recognize microbe-associated molecular patterns (MAMPs) and respond with inflammatory proteins. Simultaneous impacts of bacterial cyclic di-guanosine monophosphate (c-di-GMP), cyclic di-adenosine monophosphate (c-di-AMP), and lipopolysaccharide (LPS) on gingival keratinocytes have been previously demonstrated, but the effects of these MAMPs on other periodontal cell types, such as gingival fibroblasts, remain to be clarified. The present aim was to examine the independent and combined effects of these cyclic dinucleotides and LPS on interleukin (IL) and matrix metalloproteinase (MMP) response of HGFs. The cells were incubated with c-di-GMP and c-di-AMP, either in the presence or absence of Porphyromonas gingivalis LPS, for 2 h and 24 h. The levels of IL-8, -10, and -34, and MMP-1, -2, and -3 secreted were measured by the Luminex technique. LPS alone or together with cyclic dinucleotides elevated IL-8 levels. IL-10 levels were significantly increased in the presence of c-di-GMP and LPS after 2 h but disappeared after 24 h of incubation. Concurrent treatment of c-di-AMP and LPS elevated MMP-1 levels, whereas c-di-GMP with LPS suppressed MMP-2 levels but increased MMP-3 levels. To conclude, we produce evidence that cyclic dinucleotides interact with LPS-mediated early response of gingival fibroblasts, while late cellular response is mainly regulated by LPS.

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13

Purificação, Aline Dias da, Nathalia Marins de Azevedo, Gabriel Guarany de Araujo, Robson Francisco de Souza, and Cristiane Rodrigues Guzzo. "The World of Cyclic Dinucleotides in Bacterial Behavior." Molecules 25, no. 10 (May 25, 2020): 2462. http://dx.doi.org/10.3390/molecules25102462.

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The regulation of multiple bacterial phenotypes was found to depend on different cyclic dinucleotides (CDNs) that constitute intracellular signaling second messenger systems. Most notably, c-di-GMP, along with proteins related to its synthesis, sensing, and degradation, was identified as playing a central role in the switching from biofilm to planktonic modes of growth. Recently, this research topic has been under expansion, with the discoveries of new CDNs, novel classes of CDN receptors, and the numerous functions regulated by these molecules. In this review, we comprehensively describe the three main bacterial enzymes involved in the synthesis of c-di-GMP, c-di-AMP, and cGAMP focusing on description of their three-dimensional structures and their structural similarities with other protein families, as well as the essential residues for catalysis. The diversity of CDN receptors is described in detail along with the residues important for the interaction with the ligand. Interestingly, genomic data strongly suggest that there is a tendency for bacterial cells to use both c-di-AMP and c-di-GMP signaling networks simultaneously, raising the question of whether there is crosstalk between different signaling systems. In summary, the large amount of sequence and structural data available allows a broad view of the complexity and the importance of these CDNs in the regulation of different bacterial behaviors. Nevertheless, how cells coordinate the different CDN signaling networks to ensure adaptation to changing environmental conditions is still open for much further exploration.

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14

Bartsch, Tabea, Martin Becker, Jascha Rolf, Katrin Rosenthal, and Stephan Lütz. "Biotechnological production of cyclic dinucleotides—Challenges and opportunities." Biotechnology and Bioengineering 119, no. 3 (January 4, 2022): 677–84. http://dx.doi.org/10.1002/bit.28027.

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15

Krasteva, Petya Violinova, and Holger Sondermann. "Versatile modes of cellular regulation via cyclic dinucleotides." Nature Chemical Biology 13, no. 4 (March 22, 2017): 350–59. http://dx.doi.org/10.1038/nchembio.2337.

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16

Abdul-Sater, Ali A., Andrzej Grajkowski, Hediye Erdjument-Bromage, Courtney Plumlee, Assaf Levi, Michael T. Schreiber, Carolyn Lee, Howard Shuman, Serge L. Beaucage, and Christian Schindler. "The overlapping host responses to bacterial cyclic dinucleotides." Microbes and Infection 14, no. 2 (February 2012): 188–97. http://dx.doi.org/10.1016/j.micinf.2011.09.002.

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17

Zaver, Shivam A., and Joshua J. Woodward. "Cyclic dinucleotides at the forefront of innate immunity." Current Opinion in Cell Biology 63 (April 2020): 49–56. http://dx.doi.org/10.1016/j.ceb.2019.12.004.

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18

Li, Yao, Paul T. Ludford, Andrea Fin, Alexander R. Rovira, and Yitzhak Tor. "Enzymatic Syntheses and Applications of Fluorescent Cyclic Dinucleotides." Chemistry – A European Journal 26, no. 27 (April 28, 2020): 6076–84. http://dx.doi.org/10.1002/chem.202001194.

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19

Elmanfi, Samira, Mustafa Yilmaz, Wilson W. S. Ong, Kofi S. Yeboah, Herman O. Sintim, Mervi Gürsoy, Eija Könönen, and Ulvi K. Gürsoy. "Bacterial Cyclic Dinucleotides and the cGAS–cGAMP–STING Pathway: A Role in Periodontitis?" Pathogens 10, no. 6 (May 30, 2021): 675. http://dx.doi.org/10.3390/pathogens10060675.

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Host cells can recognize cytosolic double-stranded DNAs and endogenous second messengers as cyclic dinucleotides—including c-di-GMP, c-di-AMP, and cGAMP—of invading microbes via the critical and essential innate immune signaling adaptor molecule known as STING. This recognition activates the innate immune system and leads to the production of Type I interferons and proinflammatory cytokines. In this review, we (1) focus on the possible role of bacterial cyclic dinucleotides and the STING/TBK1/IRF3 pathway in the pathogenesis of periodontal disease and the regulation of periodontal immune response, and (2) review and discuss activators and inhibitors of the STING pathway as immune response regulators and their potential utility in the treatment of periodontitis. PubMed/Medline, Scopus, and Web of Science were searched with the terms “STING”, “TBK 1”, “IRF3”, and “cGAS”—alone, or together with “periodontitis”. Current studies produced evidence for using STING-pathway-targeting molecules as part of anticancer therapy, and as vaccine adjuvants against microbial infections; however, the role of the STING/TBK1/IRF3 pathway in periodontal disease pathogenesis is still undiscovered. Understanding the stimulation of the innate immune response by cyclic dinucleotides opens a new approach to host modulation therapies in periodontology.

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20

Chu, Jiachen, and Zhaozhu Qiu. "An anion channel for cyclic dinucleotides in T cells." Nature Immunology 23, no. 2 (February 2022): 157–58. http://dx.doi.org/10.1038/s41590-021-01118-6.

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21

Børsting, Philip, and Poul Nielsen. "Tandem ring-closing metathesis and hydrogenation towards cyclic dinucleotides." Chem. Commun., no. 18 (2002): 2140–41. http://dx.doi.org/10.1039/b206560f.

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22

Clivio, Pascale, Stéphanie Coantic-Castex, and Dominique Guillaume. "(3′-5′)-Cyclic Dinucleotides: Synthetic Strategies and Biological Potential." Chemical Reviews 113, no. 10 (June 14, 2013): 7354–401. http://dx.doi.org/10.1021/cr300011s.

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23

Brouillette, Eric, Mamoru Hyodo, Yoshihiro Hayakawa, David K. R. Karaolis, and François Malouin. "3′,5′-Cyclic Diguanylic Acid Reduces the Virulence of Biofilm-Forming Staphylococcus aureus Strains in a Mouse Model of Mastitis Infection." Antimicrobial Agents and Chemotherapy 49, no. 8 (August 2005): 3109–13. http://dx.doi.org/10.1128/aac.49.8.3109-3113.2005.

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ABSTRACT The cyclic dinucleotide 3′,5′-cyclic diguanylic acid (c-di-GMP) is a naturally occurring small molecule that regulates important signaling systems in bacteria. We have recently shown that c-di-GMP inhibits Staphylococcus aureus biofilm formation in vitro and its adherence to HeLa cells. We now report that c-di-GMP treatment has an antimicrobial and antipathogenic activity in vivo and reduces, in a dose-dependent manner, bacterial colonization by biofilm-forming S. aureus strains in a mouse model of mastitis infection. Intramammary injections of 5 and 50 nmol of c-di-GMP decreased colonization (bacterial CFU per gram of gland) by 0.79 (P > 0.05) and 1.44 (P < 0.01) logs, respectively, whereas 200-nmol doses allowed clearance of the bacteria below the detection limit with a reduction of more than 4 logs (P < 0.001) compared to the untreated control groups. These results indicate that cyclic dinucleotides potentially represent an attractive and novel drug platform which could be used alone or in combination with other agents or drugs in the prevention, treatment, or control of infection.

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24

Hallberg, Zachary F., Xin C. Wang, Todd A. Wright, Beiyan Nan, Omer Ad, Jongchan Yeo, and Ming C. Hammond. "Hybrid promiscuous (Hypr) GGDEF enzymes produce cyclic AMP-GMP (3′, 3′-cGAMP)." Proceedings of the National Academy of Sciences 113, no. 7 (February 2, 2016): 1790–95. http://dx.doi.org/10.1073/pnas.1515287113.

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Over 30 years ago, GGDEF domain-containing enzymes were shown to be diguanylate cyclases that produce cyclic di-GMP (cdiG), a second messenger that modulates the key bacterial lifestyle transition from a motile to sessile biofilm-forming state. Since then, the ubiquity of genes encoding GGDEF proteins in bacterial genomes has established the dominance of cdiG signaling in bacteria. However, the observation that proteobacteria encode a large number of GGDEF proteins, nearing 1% of coding sequences in some cases, raises the question of why bacteria need so many GGDEF enzymes. In this study, we reveal that a subfamily of GGDEF enzymes synthesizes the asymmetric signaling molecule cyclic AMP-GMP (cAG or 3′, 3′-cGAMP). This discovery is unexpected because GGDEF enzymes function as symmetric homodimers, with each monomer binding to one substrate NTP. Detailed analysis of the enzyme from Geobacter sulfurreducens showed it is a dinucleotide cyclase capable of switching the major cyclic dinucleotide (CDN) produced based on ATP-to-GTP ratios. We then establish through bioinformatics and activity assays that hybrid CDN-producing and promiscuous substrate-binding (Hypr) GGDEF enzymes are found in other deltaproteobacteria. Finally, we validated the predictive power of our analysis by showing that cAG is present in surface-grown Myxococcus xanthus. This study reveals that GGDEF enzymes make alternative cyclic dinucleotides to cdiG and expands the role of this widely distributed enzyme family to include regulation of cAG signaling.

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25

Ko, Tzu-Ping, Yu-Chuan Wang, Chia-Ling Tsai, Chia-Shin Yang, Mei-Hui Hou, and Yeh Chen. "Crystal structure and functional implication of a bacterial cyclic AMP–AMP–GMP synthetase." Nucleic Acids Research 49, no. 8 (April 9, 2021): 4725–37. http://dx.doi.org/10.1093/nar/gkab165.

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Abstract Mammalian cyclic GMP-AMP synthase (cGAS) and its homologue dinucleotide cyclase in Vibrio cholerae (VcDncV) produce cyclic dinucleotides (CDNs) that participate in the defense against viral infection. Recently, scores of new cGAS/DncV-like nucleotidyltransferases (CD-NTases) were discovered, which produce various CDNs and cyclic trinucleotides (CTNs) as second messengers. Here, we present the crystal structures of EcCdnD, a CD-NTase from Enterobacter cloacae that produces cyclic AMP-AMP-GMP, in its apo-form and in complex with ATP, ADP and AMPcPP, an ATP analogue. Despite the similar overall architecture, the protein shows significant structural variations from other CD-NTases. Adjacent to the donor substrate, another nucleotide is bound to the acceptor binding site by a non-productive mode. Isothermal titration calorimetry results also suggest the presence of two ATP binding sites. GTP alone does not bind to EcCdnD, which however binds to pppApG, a possible intermediate. The enzyme is active on ATP or a mixture of ATP and GTP, and the best metal cofactor is Mg2+. The conserved residues Asp69 and Asp71 are essential for catalysis, as indicated by the loss of activity in the mutants. Based on structural analysis and comparison with VcDncV and RNA polymerase, a tentative catalytic pathway for the CTN-producing EcCdnD is proposed.

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26

Fujino, Tomoko, Koudai Okada, and Hiroyuki Isobe. "Conformational restriction of cyclic dinucleotides with triazole-linked cyclophane analogues." Tetrahedron Letters 55, no. 16 (April 2014): 2659–61. http://dx.doi.org/10.1016/j.tetlet.2014.03.026.

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27

Elmanfi, Samira, Jie Zhou, Herman O. Sintim, Eija Könönen, Mervi Gürsoy, and Ulvi Kahraman Gürsoy. "Regulation of gingival epithelial cytokine response by bacterial cyclic dinucleotides." Journal of Oral Microbiology 11, no. 1 (November 27, 2018): 1538927. http://dx.doi.org/10.1080/20002297.2018.1538927.

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28

Bowie, Andrew G. "Innate sensing of bacterial cyclic dinucleotides: more than just STING." Nature Immunology 13, no. 12 (November 16, 2012): 1137–39. http://dx.doi.org/10.1038/ni.2469.

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Karaolis, David K. R., Mohammed H. Rashid, Rajanna Chythanya, Wensheng Luo, Mamoru Hyodo, and Yoshihiro Hayakawa. "c-di-GMP (3′-5′-Cyclic Diguanylic Acid) Inhibits Staphylococcus aureus Cell-Cell Interactions and Biofilm Formation." Antimicrobial Agents and Chemotherapy 49, no. 3 (March 2005): 1029–38. http://dx.doi.org/10.1128/aac.49.3.1029-1038.2005.

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ABSTRACT Staphylococcus aureus is an important pathogen of humans and animals, and antibiotic resistance is a public health concern. Biofilm formation is essential in virulence and pathogenesis, and the ability to resist antibiotic treatment results in difficult-to-treat and persistent infections. As such, novel antimicrobial approaches are of great interest to the scientific, medical, and agriculture communities. We recently proposed that modulating levels of the cyclic dinucleotide signaling molecule, c-di-GMP (cyclic diguanylate [3′,5′-cyclic diguanylic acid], cGpGp), has utility in regulating phenotypes of prokaryotes. We report that extracellular c-di-GMP shows activity against human clinical and bovine intramammary mastitis isolates of S. aureus, including methicillin-resistant S. aureus (MRSA) isolates. We show that chemically synthesized c-di-GMP is soluble and stable in water and physiological saline and stable following boiling and exposure to acid and alkali. Treatment of S. aureus with extracellular c-di-GMP inhibited cell-to-cell (intercellular) adhesive interactions in liquid medium and reduced (>50%) biofilm formation in human and bovine isolates compared to untreated controls. c-di-GMP inhibited the adherence of S. aureus to human epithelial HeLa cells. The cyclic nucleotide analogs cyclic GMP and cyclic AMP had a lesser inhibitory effect on biofilms, while 5′-GMP had no major effect. We propose that cyclic dinucleotides such as c-di-GMP, used either alone or in combination with other antimicrobial agents, represent a novel and attractive approach in the development of intervention strategies for the prevention of biofilms and the control and treatment of infection.

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Nelson, James W., Narasimhan Sudarsan, Grace E. Phillips, Shira Stav, Christina E. Lünse, Phillip J. McCown, and Ronald R. Breaker. "Control of bacterial exoelectrogenesis by c-AMP-GMP." Proceedings of the National Academy of Sciences 112, no. 17 (April 6, 2015): 5389–94. http://dx.doi.org/10.1073/pnas.1419264112.

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Major changes in bacterial physiology including biofilm and spore formation involve signaling by the cyclic dinucleotides c-di-GMP and c-di-AMP. Recently, another second messenger dinucleotide, c-AMP-GMP, was found to control chemotaxis and colonization by Vibrio cholerae. We have identified a superregulon of genes controlled by c-AMP-GMP in numerous Deltaproteobacteria, including Geobacter species that use extracellular insoluble metal oxides as terminal electron acceptors. This exoelectrogenic process has been studied for its possible utility in energy production and bioremediation. Many genes involved in adhesion, pilin formation, and others that are important for exoelectrogenesis are controlled by members of a variant riboswitch class that selectively bind c-AMP-GMP. These RNAs constitute, to our knowledge, the first known specific receptors for c-AMP-GMP and reveal that this molecule is used by many bacteria to control specialized physiological processes.

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Gogoi, Himanshu, Samira Mansouri, and Lei Jin. "The Age of Cyclic Dinucleotide Vaccine Adjuvants." Vaccines 8, no. 3 (August 13, 2020): 453. http://dx.doi.org/10.3390/vaccines8030453.

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As prophylactic vaccine adjuvants for infectious diseases, cyclic dinucleotides (CDNs) induce safe, potent, long-lasting humoral and cellular memory responses in the systemic and mucosal compartments. As therapeutic cancer vaccine adjuvants, CDNs induce potent anti-tumor immunity, including cytotoxic T cells and NK cells activation that achieve durable regression in multiple mouse models of tumors. Clinical trials are ongoing to fulfill the promise of CDNs (ClinicalTrials.gov: NCT02675439, NCT03010176, NCT03172936, and NCT03937141). However, in October 2018, the first clinical data with Merck’s CDN MK-1454 showed zero activity as a monotherapy in patients with solid tumors or lymphomas (NCT03010176). Lately, the clinical trial from Aduro’s CDN ADU-S100 monotherapy was also disappointing (NCT03172936). The emerging hurdle in CDN vaccine development calls for a timely re-evaluation of our understanding on CDN vaccine adjuvants. Here, we review the status of CDN vaccine adjuvant research, including their superior adjuvant activities, in vivo mode of action, and confounding factors that affect their efficacy in humans. Lastly, we discuss the strategies to overcome the hurdle and advance promising CDN adjuvants in humans.

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32

Segrist, Elisha, Mark Dittmar, Beth Gold, and Sara Cherry. "Orally acquired cyclic dinucleotides drive dSTING-dependent antiviral immunity in enterocytes." Cell Reports 37, no. 13 (December 2021): 110150. http://dx.doi.org/10.1016/j.celrep.2021.110150.

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33

Fei, Na, Daniel Häussinger, Seraina Blümli, Benoît-Joseph Laventie, Lorenzo D. Bizzini, Kaspar Zimmermann, Urs Jenal, and Dennis Gillingham. "Catalytic carbene transfer allows the direct customization of cyclic purine dinucleotides." Chemical Communications 50, no. 62 (June 20, 2014): 8499. http://dx.doi.org/10.1039/c4cc01919a.

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34

Che, Xing, Jun Zhang, Yanyu Zhu, Lijiang Yang, Hui Quan, and Yi Qin Gao. "Structural Flexibility and Conformation Features of Cyclic Dinucleotides in Aqueous Solutions." Journal of Physical Chemistry B 120, no. 10 (March 3, 2016): 2670–80. http://dx.doi.org/10.1021/acs.jpcb.5b11531.

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35

Zeng, Fan, and Roger A. Jones. "SYNTHESIS OF CYCLIC DINUCLEOTIDES BY AN H-PHOSPHONATE METHOD IN SOLUTION." Nucleosides and Nucleotides 15, no. 11-12 (November 1996): 1679–86. http://dx.doi.org/10.1080/07328319608002723.

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36

Fu, Juan, Young Kim, David Kanne, Meredith Leong, Qi Zeng, Rupashree Sen, Todd D. Amstrong, et al. "Cyclic dinucleotides (CDNs) reversed T cells tolerance in anti-tumor immunotherapy." Journal for ImmunoTherapy of Cancer 3, Suppl 2 (2015): P268. http://dx.doi.org/10.1186/2051-1426-3-s2-p268.

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37

Kwon, Yeongkag, Ok‐Jin Park, Jiseon Kim, Jae‐Ho Cho, Cheol‐Heui Yun та Seung Hyun Han. "Cyclic Dinucleotides Inhibit Osteoclast Differentiation Through STING‐Mediated Interferon‐β Signaling". Journal of Bone and Mineral Research 34, № 7 (6 березня 2019): 1366–75. http://dx.doi.org/10.1002/jbmr.3701.

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38

Tosolini, Marie, Frédéric Pont, Els Verhoeyen, and Jean-Jacques Fournié. "Cyclic dinucleotides modulate human T-cell response through monocyte cell death." European Journal of Immunology 45, no. 12 (October 15, 2015): 3313–23. http://dx.doi.org/10.1002/eji.201545697.

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39

Clivio, Pascale, Stephanie Coantic-Castex, and Dominique Guillaume. "ChemInform Abstract: (3′-5′)-Cyclic Dinucleotides: Synthetic Strategies and Biological Potential." ChemInform 44, no. 48 (November 8, 2013): no. http://dx.doi.org/10.1002/chin.201348237.

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40

Wang, Zhenghua, and Zhen Xi. "Chemical evolution of cyclic dinucleotides: Perspective of the analogs and their preparation." Tetrahedron 87 (May 2021): 132096. http://dx.doi.org/10.1016/j.tet.2021.132096.

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41

Sørensen, Anders M., Katrine E. Nielsen, Barbara Vogg, Jens Peter Jacobsen, and Poul Nielsen. "Synthesis and NMR-studies of dinucleotides with conformationally restricted cyclic phosphotriester linkages." Tetrahedron 57, no. 51 (December 2001): 10191–201. http://dx.doi.org/10.1016/s0040-4020(01)01047-x.

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42

Winnerdy, Fernaldo Richtia, Poulomi Das, Brahim Heddi, and Anh Tuân Phan. "Solution Structures of a G-Quadruplex Bound to Linear- and Cyclic-Dinucleotides." Journal of the American Chemical Society 141, no. 45 (October 29, 2019): 18038–47. http://dx.doi.org/10.1021/jacs.9b05642.

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43

Li, Yao, Andrea Fin, Alexander R. Rovira, Yichi Su, Andrew B. Dippel, Jonathan Andrés Valderrama, Angelica M. Riestra, Victor Nizet, Ming C. Hammond, and Yitzhak Tor. "Tuning the Innate Immune Response to Cyclic Dinucleotides by Using Atomic Mutagenesis." ChemBioChem 21, no. 18 (June 8, 2020): 2595–98. http://dx.doi.org/10.1002/cbic.202000162.

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44

McFarland, Adelle, Shukun Luo, Fariha Ahmed-Qadri, Elizabeth F. Thayer, Hannah Tabakh, Liang Tong, and Joshua J. Woodward. "Cyclic dinucleotide detection by RECON controls innate immune responses." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 132.1. http://dx.doi.org/10.4049/jimmunol.196.supp.132.1.

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Анотація:

Abstract Host cells have evolved a sophisticated arsenal of germ-line encoded pattern recognition receptors that detect a vast array of microorganisms in distinct tissues and cellular compartments. Cytoplasmic sensors monitor for microbes that gain access to the host cell cytosol following breach of the plasma membrane or intracellular invasion. This sensing is achieved through detection of invariant molecular patterns associated with microorganisms or cell stress responses that indicate the presence of a pathogen. Cyclic dinucleotides (cdNs) of both bacterial and host origin have emerged as important molecules that are sensed during infection. Details about the receptors cdNs engage in host cells and the responses those interactions elicit are just coming to light. We have recently discovered the first bacterial cdN-specific pattern recognition receptor, the oxidoreductase RECON. Our work on this receptor has revealed its central role in directing innate immune responses when engaged by bacterial cdNs. These findings reveal a new pattern recognition receptor specific for bacterial cdNs that orchestrates cytosolic immune surveillance by shaping downstream inflammatory gene activation.

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45

Yan, Hongbin, and Wangxue Chen. "The Promise and Challenges of Cyclic Dinucleotides as Molecular Adjuvants for Vaccine Development." Vaccines 9, no. 8 (August 17, 2021): 917. http://dx.doi.org/10.3390/vaccines9080917.

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Cyclic dinucleotides (CDNs), originally discovered as bacterial second messengers, play critical roles in bacterial signal transduction, cellular processes, biofilm formation, and virulence. The finding that CDNs can trigger the innate immune response in eukaryotic cells through the stimulator of interferon genes (STING) signalling pathway has prompted the extensive research and development of CDNs as potential immunostimulators and novel molecular adjuvants for induction of systemic and mucosal innate and adaptive immune responses. In this review, we summarize the chemical structure, biosynthesis regulation, and the role of CDNs in enhancing the crosstalk between host innate and adaptive immune responses. We also discuss the strategies to improve the efficient delivery of CDNs and the recent advance and future challenges in the development of CDNs as potential adjuvants in prophylactic vaccines against infectious diseases and in therapeutic vaccines against cancers.

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46

Chang, Denis, Aaron T. Whiteley, Katlynn Bugda Gwilt, Wayne I. Lencer, John J. Mekalanos, and Jay R. Thiagarajah. "Extracellular cyclic dinucleotides induce polarized responses in barrier epithelial cells by adenosine signaling." Proceedings of the National Academy of Sciences 117, no. 44 (October 21, 2020): 27502–8. http://dx.doi.org/10.1073/pnas.2015919117.

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Cyclic dinucleotides (CDNs) are secondary messengers used by prokaryotic and eukaryotic cells. In mammalian cells, cytosolic CDNs bind STING (stimulator of IFN gene), resulting in the production of type I IFN. Extracellular CDNs can enter the cytosol through several pathways but how CDNs work from outside eukaryotic cells remains poorly understood. Here, we elucidate a mechanism of action on intestinal epithelial cells for extracellular CDNs. We found that CDNs containing adenosine induced a robust CFTR-mediated chloride secretory response together with cAMP-mediated inhibition of Poly I:C-stimulated IFNβ expression. Signal transduction was strictly polarized to the serosal side of the epithelium, dependent on the extracellular and sequential hydrolysis of CDNs to adenosine by the ectonucleosidases ENPP1 and CD73, and occurred via activation of A2Badenosine receptors. These studies highlight a pathway by which microbial and host produced extracellular CDNs can regulate the innate immune response of barrier epithelial cells lining mucosal surfaces.

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47

Lolicato, Marco, Annalisa Bucchi, Cristina Arrigoni, Stefano Zucca, Marco Nardini, Indra Schroeder, Katie Simmons, et al. "Cyclic dinucleotides bind the C-linker of HCN4 to control channel cAMP responsiveness." Nature Chemical Biology 10, no. 6 (April 28, 2014): 457–62. http://dx.doi.org/10.1038/nchembio.1521.

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48

ZENG, F., and R. A. JONES. "ChemInform Abstract: Synthesis of Cyclic Dinucleotides by a H-Phosphonate Method in Solution." ChemInform 28, no. 38 (August 3, 2010): no. http://dx.doi.org/10.1002/chin.199738260.

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49

Motedayen Aval, Leila, James E. Pease, Rohini Sharma, and David J. Pinato. "Challenges and Opportunities in the Clinical Development of STING Agonists for Cancer Immunotherapy." Journal of Clinical Medicine 9, no. 10 (October 16, 2020): 3323. http://dx.doi.org/10.3390/jcm9103323.

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Immune checkpoint inhibitors (ICI) have revolutionised cancer therapy. However, they have been effective in only a small subset of patients and a principal mechanism underlying immune-refractoriness is a ‘cold’ tumour microenvironment, that is, lack of a T-cell-rich, spontaneously inflamed phenotype. As such, there is a demand to develop strategies to transform the tumour milieu of non-responsive patients to one supporting T-cell-based inflammation. The cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway is a fundamental regulator of innate immune sensing of cancer, with potential to enhance tumour rejection through the induction of a pro-inflammatory response dominated by Type I interferons. Recognition of these positive immune-modulatory properties has rapidly elevated the STING pathway as a putative target for immunotherapy, leading to a myriad of preclinical and clinical studies assessing natural and synthetic cyclic dinucleotides and non-nucleotidyl STING agonists. Despite pre-clinical evidence of efficacy, clinical translation has resulted into disappointingly modest efficacy. Poor pharmacokinetic and physiochemical properties of cyclic dinucleotides are key barriers to the development of STING agonists, most of which require intra-tumoral dosing. Development of systemically administered non-nucleotidyl STING agonists, or conjugation with liposomes, polymers and hydrogels may overcome pharmacokinetic limitations and improve drug delivery. In this review, we summarise the body of evidence supporting a synergistic role of STING agonists with currently approved ICI therapies and discuss whether, despite the numerous obstacles encountered to date, the clinical development of STING agonist as novel anti-cancer therapeutics may still hold the promise of broadening the reach of cancer immunotherapy.

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50

Reddy, Swetha, Gokul Turaga, Hossam Abdelhamed, Michelle M. Banes, Robert W. Wills, and Mark L. Lawrence. "Listeria monocytogenes PdeE, a phosphodiesterase that contributes to virulence and has hydrolytic activity against cyclic mononucleotides and cyclic dinucleotides." Microbial Pathogenesis 110 (September 2017): 399–408. http://dx.doi.org/10.1016/j.micpath.2017.07.020.

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