Development of human cGAS-specific small-molecule inhibitors for repression of dsDNA-triggered interferon expression
Abstract
Cyclic GMP-AMP synthase (cGAS) is the primary sensor for aberrant intracellular dsDNA producing the cyclic dinucleotide cGAMP, a second messenger initiating cytokine production in subsets of myeloid lineage cell types. Therefore, inhibition of the enzyme cGAS may act anti-inflammatory. Here we report the discovery of human-cGAS-specific small-molecule inhibitors by high-throughput screening and the targeted medicinal chemistry optimization for two molecular scaffolds. Lead compounds from one scaffold co-crystallize with human cGAS and occupy the ATP- and GTP-binding active site. The specificity and potency of these drug candidates is further documented in human myeloid cells including primary macrophages. These novel cGAS inhibitors with cell-based activity will serve as probes into cGAS-dependent innate immune pathways and warrant future pharmacological studies for treatment of cGAS-dependent inflammatory diseases.
- Authors:
-
[2];
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- Rockefeller Univ., New York, NY (United States)
- Memorial Sloan-Kettering Cancer Center, New York, NY (United States)
- Tri-Institutional Therapeutics Discovery Inst., New York, NY (United States)
- Chinese Academy of Sciences (CAS), Beijing (China); Memorial Sloan-Kettering Cancer Center, New York, NY (United States)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- Takeda Pharmaceutical Company; Memorial Sloan Kettering Cancer Center; The Rockefeller Univ., Weill Cornell Medicine
- OSTI Identifier:
- 1524667
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nature Communications
- Additional Journal Information:
- Journal Volume: 10; Journal Issue: 1; Journal ID: ISSN 2041-1723
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; High-throughput screening; Pattern recognition receptors
Citation Formats
Lama, Lodoe, Adura, Carolina, Xie, Wei, Tomita, Daisuke, Kamei, Taku, Kuryavyi, Vitaly, Gogakos, Tasos, Steinberg, Joshua I., Miller, Michael, Ramos-Espiritu, Lavoisier, Asano, Yasutomi, Hashizume, Shogo, Aida, Jumpei, Imaeda, Toshihiro, Okamoto, Rei, Jennings, Andy J., Michino, Mayako, Kuroita, Takanobu, Stamford, Andrew, Gao, Pu, Meinke, Peter, Glickman, J. Fraser, Patel, Dinshaw J., and Tuschl, Thomas. Development of human cGAS-specific small-molecule inhibitors for repression of dsDNA-triggered interferon expression. United States: N. p., 2019.
Web. doi:10.1038/s41467-019-08620-4.
Lama, Lodoe, Adura, Carolina, Xie, Wei, Tomita, Daisuke, Kamei, Taku, Kuryavyi, Vitaly, Gogakos, Tasos, Steinberg, Joshua I., Miller, Michael, Ramos-Espiritu, Lavoisier, Asano, Yasutomi, Hashizume, Shogo, Aida, Jumpei, Imaeda, Toshihiro, Okamoto, Rei, Jennings, Andy J., Michino, Mayako, Kuroita, Takanobu, Stamford, Andrew, Gao, Pu, Meinke, Peter, Glickman, J. Fraser, Patel, Dinshaw J., & Tuschl, Thomas. Development of human cGAS-specific small-molecule inhibitors for repression of dsDNA-triggered interferon expression. United States. https://doi.org/10.1038/s41467-019-08620-4
Lama, Lodoe, Adura, Carolina, Xie, Wei, Tomita, Daisuke, Kamei, Taku, Kuryavyi, Vitaly, Gogakos, Tasos, Steinberg, Joshua I., Miller, Michael, Ramos-Espiritu, Lavoisier, Asano, Yasutomi, Hashizume, Shogo, Aida, Jumpei, Imaeda, Toshihiro, Okamoto, Rei, Jennings, Andy J., Michino, Mayako, Kuroita, Takanobu, Stamford, Andrew, Gao, Pu, Meinke, Peter, Glickman, J. Fraser, Patel, Dinshaw J., and Tuschl, Thomas. Tue .
"Development of human cGAS-specific small-molecule inhibitors for repression of dsDNA-triggered interferon expression". United States. https://doi.org/10.1038/s41467-019-08620-4. https://www.osti.gov/servlets/purl/1524667.
@article{osti_1524667,
title = {Development of human cGAS-specific small-molecule inhibitors for repression of dsDNA-triggered interferon expression},
author = {Lama, Lodoe and Adura, Carolina and Xie, Wei and Tomita, Daisuke and Kamei, Taku and Kuryavyi, Vitaly and Gogakos, Tasos and Steinberg, Joshua I. and Miller, Michael and Ramos-Espiritu, Lavoisier and Asano, Yasutomi and Hashizume, Shogo and Aida, Jumpei and Imaeda, Toshihiro and Okamoto, Rei and Jennings, Andy J. and Michino, Mayako and Kuroita, Takanobu and Stamford, Andrew and Gao, Pu and Meinke, Peter and Glickman, J. Fraser and Patel, Dinshaw J. and Tuschl, Thomas},
abstractNote = {Cyclic GMP-AMP synthase (cGAS) is the primary sensor for aberrant intracellular dsDNA producing the cyclic dinucleotide cGAMP, a second messenger initiating cytokine production in subsets of myeloid lineage cell types. Therefore, inhibition of the enzyme cGAS may act anti-inflammatory. Here we report the discovery of human-cGAS-specific small-molecule inhibitors by high-throughput screening and the targeted medicinal chemistry optimization for two molecular scaffolds. Lead compounds from one scaffold co-crystallize with human cGAS and occupy the ATP- and GTP-binding active site. The specificity and potency of these drug candidates is further documented in human myeloid cells including primary macrophages. These novel cGAS inhibitors with cell-based activity will serve as probes into cGAS-dependent innate immune pathways and warrant future pharmacological studies for treatment of cGAS-dependent inflammatory diseases.},
doi = {10.1038/s41467-019-08620-4},
journal = {Nature Communications},
number = 1,
volume = 10,
place = {United States},
year = {Tue May 21 00:00:00 EDT 2019},
month = {Tue May 21 00:00:00 EDT 2019}
}
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Works referenced in this record:
Mitotic progression following DNA damage enables pattern recognition within micronuclei
journal, July 2017
- Harding, Shane M.; Benci, Joseph L.; Irianto, Jerome
- Nature, Vol. 548, Issue 7668
Structure of the Human cGAS–DNA Complex Reveals Enhanced Control of Immune Surveillance
journal, July 2018
- Zhou, Wen; Whiteley, Aaron T.; de Oliveira Mann, Carina C.
- Cell, Vol. 174, Issue 2
Cyclic GMP-AMP Containing Mixed Phosphodiester Linkages Is An Endogenous High-Affinity Ligand for STING
journal, July 2013
- Zhang, Xu; Shi, Heping; Wu, Jiaxi
- Molecular Cell, Vol. 51, Issue 2
Anti-DNA antibodies — quintessential biomarkers of SLE
journal, November 2015
- Pisetsky, David S.
- Nature Reviews Rheumatology, Vol. 12, Issue 2
Listeria monocytogenes induces IFNβ expression through an IFI16‐, cGAS‐ and STING‐dependent pathway
journal, June 2014
- Hansen, Kathrine; Prabakaran, Thaneas; Laustsen, Anders
- The EMBO Journal, Vol. 33, Issue 15
Orchestrating the interferon antiviral response through the mitochondrial antiviral signaling (MAVS) adapter
journal, October 2011
- Belgnaoui, S. Mehdi; Paz, Suzanne; Hiscott, John
- Current Opinion in Immunology, Vol. 23, Issue 5
The Cytosolic Sensor cGAS Detects Mycobacterium tuberculosis DNA to Induce Type I Interferons and Activate Autophagy
journal, June 2015
- Watson, Robert O.; Bell, Samantha L.; MacDuff, Donna A.
- Cell Host & Microbe, Vol. 17, Issue 6
An RNA-Based Fluorescent Biosensor for High-Throughput Analysis of the cGAS-cGAMP-STING Pathway
journal, December 2016
- Bose, Debojit; Su, Yichi; Marcus, Assaf
- Cell Chemical Biology, Vol. 23, Issue 12
Targeting STING with covalent small-molecule inhibitors
journal, July 2018
- Haag, Simone M.; Gulen, Muhammet F.; Reymond, Luc
- Nature, Vol. 559, Issue 7713
OAS proteins and cGAS: unifying concepts in sensing and responding to cytosolic nucleic acids
journal, July 2014
- Hornung, Veit; Hartmann, Rune; Ablasser, Andrea
- Nature Reviews Immunology, Vol. 14, Issue 8
Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence
journal, July 2017
- Glück, Selene; Guey, Baptiste; Gulen, Muhammet Fatih
- Nature Cell Biology, Vol. 19, Issue 9
STING manifests self DNA-dependent inflammatory disease
journal, November 2012
- Ahn, J.; Gutman, D.; Saijo, S.
- Proceedings of the National Academy of Sciences, Vol. 109, Issue 47
New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays
journal, April 2010
- Baell, Jonathan B.; Holloway, Georgina A.
- Journal of Medicinal Chemistry, Vol. 53, Issue 7
cGAS is essential for cellular senescence
journal, May 2017
- Yang, Hui; Wang, Hanze; Ren, Junyao
- Proceedings of the National Academy of Sciences, Vol. 114, Issue 23
cGAS surveillance of micronuclei links genome instability to innate immunity
journal, July 2017
- Mackenzie, Karen J.; Carroll, Paula; Martin, Carol-Anne
- Nature, Vol. 548, Issue 7668
Cyclic GMP-AMP Synthase Is a Cytosolic DNA Sensor That Activates the Type I Interferon Pathway
journal, December 2012
- Sun, L.; Wu, J.; Du, F.
- Science, Vol. 339, Issue 6121
Cyclic GMP-AMP Synthase Is an Innate Immune Sensor of HIV and Other Retroviruses
journal, August 2013
- Gao, D.; Wu, J.; Wu, Y. -T.
- Science, Vol. 341, Issue 6148
Suramin potently inhibits cGAMP synthase, cGAS, in THP1 cells to modulate IFN-β levels
journal, June 2018
- Wang, Modi; Sooreshjani, Moloud A.; Mikek, Clinton
- Future Medicinal Chemistry, Vol. 10, Issue 11
Activation of RNase L is dependent on OAS3 expression during infection with diverse human viruses
journal, February 2016
- Li, Yize; Banerjee, Shuvojit; Wang, Yuyan
- Proceedings of the National Academy of Sciences, Vol. 113, Issue 8
Small molecule inhibition of cGAS reduces interferon expression in primary macrophages from autoimmune mice
journal, September 2017
- Vincent, Jessica; Adura, Carolina; Gao, Pu
- Nature Communications, Vol. 8, Issue 1
Towards automated crystallographic structure refinement with phenix.refine
journal, March 2012
- Afonine, Pavel V.; Grosse-Kunstleve, Ralf W.; Echols, Nathaniel
- Acta Crystallographica Section D Biological Crystallography, Vol. 68, Issue 4
PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010
- Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221
The Adaptor Protein MITA Links Virus-Sensing Receptors to IRF3 Transcription Factor Activation
journal, October 2008
- Zhong, Bo; Yang, Yan; Li, Shu
- Immunity, Vol. 29, Issue 4
Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases
journal, September 2015
- Gao, Daxing; Li, Tuo; Li, Xiao-Dong
- Proceedings of the National Academy of Sciences, Vol. 112, Issue 42
ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization
journal, May 2009
- Sun, W.; Li, Y.; Chen, L.
- Proceedings of the National Academy of Sciences, Vol. 106, Issue 21
Cyclic [G(2′,5′)pA(3′,5′)p] Is the Metazoan Second Messenger Produced by DNA-Activated Cyclic GMP-AMP Synthase
journal, May 2013
- Gao, Pu; Ascano, Manuel; Wu, Yang
- Cell, Vol. 153, Issue 5
The E3 Ubiquitin Ligase AMFR and INSIG1 Bridge the Activation of TBK1 Kinase by Modifying the Adaptor STING
journal, December 2014
- Wang, Qiang; Liu, Xing; Cui, Ye
- Immunity, Vol. 41, Issue 6
Discovery of LRE1 as a specific and allosteric inhibitor of soluble adenylyl cyclase
journal, August 2016
- Ramos-Espiritu, Lavoisier; Kleinboelting, Silke; Navarrete, Felipe A.
- Nature Chemical Biology, Vol. 12, Issue 10
cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING
journal, May 2013
- Ablasser, Andrea; Goldeck, Marion; Cavlar, Taner
- Nature, Vol. 498, Issue 7454
Cytosolic-DNA-Mediated, STING-Dependent Proinflammatory Gene Induction Necessitates Canonical NF- B Activation through TBK1
journal, March 2014
- Abe, T.; Barber, G. N.
- Journal of Virology, Vol. 88, Issue 10
Modulation of the cGAS-STING DNA sensing pathway by gammaherpesviruses
journal, July 2015
- Ma, Zhe; Jacobs, Sarah R.; West, John A.
- Proceedings of the National Academy of Sciences, Vol. 112, Issue 31
Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus
journal, July 2006
- Crow, Yanick J.; Hayward, Bruce E.; Parmar, Rekha
- Nature Genetics, Vol. 38, Issue 8
A Simple Statistical Parameter for Use in Evaluation and Validation of High Throughput Screening Assays
journal, April 1999
- Zhang, J. -H.
- Journal of Biomolecular Screening, Vol. 4, Issue 2
Nucleic Acid Recognition by the Innate Immune System
journal, April 2011
- Barbalat, Roman; Ewald, Sarah E.; Mouchess, Maria L.
- Annual Review of Immunology, Vol. 29, Issue 1
Mitochondrial DNA stress primes the antiviral innate immune response
journal, February 2015
- West, A. Phillip; Khoury-Hanold, William; Staron, Matthew
- Nature, Vol. 520, Issue 7548
High-Throughput Screening with Quantitation of ATP Consumption: A Universal Non-Radioisotope, Homogeneous Assay for Protein Kinase
journal, April 2004
- Koresawa, Mitsunori; Okabe, Takayoshi
- ASSAY and Drug Development Technologies, Vol. 2, Issue 2
Discovery of PF-06928215 as a high affinity inhibitor of cGAS enabled by a novel fluorescence polarization assay
journal, September 2017
- Hall, Justin; Brault, Amy; Vincent, Fabien
- PLOS ONE, Vol. 12, Issue 9
Molecular similarity: a key technique in molecular informatics
journal, January 2004
- Bender, Andreas; Glen, Robert C.
- Organic & Biomolecular Chemistry, Vol. 2, Issue 22
UCSF Chimera?A visualization system for exploratory research and analysis
journal, January 2004
- Pettersen, Eric F.; Goddard, Thomas D.; Huang, Conrad C.
- Journal of Computational Chemistry, Vol. 25, Issue 13
Discriminating self from non-self in nucleic acid sensing
journal, July 2016
- Schlee, Martin; Hartmann, Gunther
- Nature Reviews Immunology, Vol. 16, Issue 9
STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity
journal, September 2009
- Ishikawa, Hiroki; Ma, Zhe; Barber, Glen N.
- Nature, Vol. 461, Issue 7265
Cyclic GMP-AMP Is an Endogenous Second Messenger in Innate Immune Signaling by Cytosolic DNA
journal, December 2012
- Wu, J.; Sun, L.; Chen, X.
- Science, Vol. 339, Issue 6121
Cutting Edge: cGAS Is Required for Lethal Autoimmune Disease in the Trex1-Deficient Mouse Model of Aicardi–Goutières Syndrome
journal, July 2015
- Gray, Elizabeth E.; Treuting, Piper M.; Woodward, Joshua J.
- The Journal of Immunology, Vol. 195, Issue 5
Cutting Edge: Antimalarial Drugs Inhibit IFN-β Production through Blockade of Cyclic GMP-AMP Synthase–DNA Interaction
journal, March 2015
- An, Jie; Woodward, Joshua J.; Sasaki, Tomikazu
- The Journal of Immunology, Vol. 194, Issue 9
Molecular Similarity: A Key Technique in Molecular Informatics.
journal, April 2005
- Bender, Andreas; Glen, Robert C.
- ChemInform, Vol. 36, Issue 15
PARP1 exhibits enhanced association and catalytic efficiency with γH2A.X-nucleosome
journal, December 2019
- Sharma, Deepti; De Falco, Louis; Padavattan, Sivaraman
- Nature Communications, Vol. 10, Issue 1
Cavin1 intrinsically disordered domains are essential for fuzzy electrostatic interactions and caveola formation
journal, February 2021
- Tillu, Vikas A.; Rae, James; Gao, Ya
- Nature Communications, Vol. 12, Issue 1
Modulation of the cGAS-STING DNA sensing pathway by gammaherpesviruses
text, January 2015
- Charles, Stopford,; Zhigang, Zhang,; R., Jacobs, Sarah
- The University of North Carolina at Chapel Hill University Libraries
PHENIX: a comprehensive Python-based system for macromolecular structure solution.
text, January 2010
- Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
- Apollo - University of Cambridge Repository
Structure of the Human cGAS–DNA Complex Reveals Enhanced Control of Immune Surveillance
journal, July 2018
- Zhou, Wen; Whiteley, Aaron T.; de Oliveira Mann, Carina C.
- Cell, Vol. 174, Issue 2
An RNA-Based Fluorescent Biosensor for High-Throughput Analysis of the cGAS-cGAMP-STING Pathway
journal, December 2016
- Bose, Debojit; Su, Yichi; Marcus, Assaf
- Cell Chemical Biology, Vol. 23, Issue 12
The Cytosolic Sensor cGAS Detects Mycobacterium tuberculosis DNA to Induce Type I Interferons and Activate Autophagy
journal, June 2015
- Watson, Robert O.; Bell, Samantha L.; MacDuff, Donna A.
- Cell Host & Microbe, Vol. 17, Issue 6
Orchestrating the interferon antiviral response through the mitochondrial antiviral signaling (MAVS) adapter
journal, October 2011
- Belgnaoui, S. Mehdi; Paz, Suzanne; Hiscott, John
- Current Opinion in Immunology, Vol. 23, Issue 5
Cell Biology: When Your Own Chromosomes Act like Foreign DNA
journal, November 2017
- Spektor, Alexander; Umbreit, Neil T.; Pellman, David
- Current Biology, Vol. 27, Issue 22
The Adaptor Protein MITA Links Virus-Sensing Receptors to IRF3 Transcription Factor Activation
journal, October 2008
- Zhong, Bo; Yang, Yan; Li, Shu
- Immunity, Vol. 29, Issue 4
The E3 Ubiquitin Ligase AMFR and INSIG1 Bridge the Activation of TBK1 Kinase by Modifying the Adaptor STING
journal, December 2014
- Wang, Qiang; Liu, Xing; Cui, Ye
- Immunity, Vol. 41, Issue 6
New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays
journal, April 2010
- Baell, Jonathan B.; Holloway, Georgina A.
- Journal of Medicinal Chemistry, Vol. 53, Issue 7
Building unique bonds to fight misplaced DNA
journal, June 2013
- Fagundes, Caio T.; O'Neill, Luke A. J.
- Cell Research, Vol. 23, Issue 9
STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity
journal, September 2009
- Ishikawa, Hiroki; Ma, Zhe; Barber, Glen N.
- Nature, Vol. 461, Issue 7265
cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING
journal, May 2013
- Ablasser, Andrea; Goldeck, Marion; Cavlar, Taner
- Nature, Vol. 498, Issue 7454
Mitochondrial DNA stress primes the antiviral innate immune response
journal, February 2015
- West, A. Phillip; Khoury-Hanold, William; Staron, Matthew
- Nature, Vol. 520, Issue 7548
Mitotic progression following DNA damage enables pattern recognition within micronuclei
journal, July 2017
- Harding, Shane M.; Benci, Joseph L.; Irianto, Jerome
- Nature, Vol. 548, Issue 7668
Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence
journal, July 2017
- Glück, Selene; Guey, Baptiste; Gulen, Muhammet Fatih
- Nature Cell Biology, Vol. 19, Issue 9
Discovery of LRE1 as a specific and allosteric inhibitor of soluble adenylyl cyclase
journal, August 2016
- Ramos-Espiritu, Lavoisier; Kleinboelting, Silke; Navarrete, Felipe A.
- Nature Chemical Biology, Vol. 12, Issue 10
Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus
journal, July 2006
- Crow, Yanick J.; Hayward, Bruce E.; Parmar, Rekha
- Nature Genetics, Vol. 38, Issue 8
OAS proteins and cGAS: unifying concepts in sensing and responding to cytosolic nucleic acids
journal, July 2014
- Hornung, Veit; Hartmann, Rune; Ablasser, Andrea
- Nature Reviews Immunology, Vol. 14, Issue 8
Anti-DNA antibodies — quintessential biomarkers of SLE
journal, November 2015
- Pisetsky, David S.
- Nature Reviews Rheumatology, Vol. 12, Issue 2
Small molecule inhibition of cGAS reduces interferon expression in primary macrophages from autoimmune mice
journal, September 2017
- Vincent, Jessica; Adura, Carolina; Gao, Pu
- Nature Communications, Vol. 8, Issue 1
Molecular similarity: a key technique in molecular informatics
journal, January 2004
- Bender, Andreas; Glen, Robert C.
- Organic & Biomolecular Chemistry, Vol. 2, Issue 22
ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization
journal, May 2009
- Sun, W.; Li, Y.; Chen, L.
- Proceedings of the National Academy of Sciences, Vol. 106, Issue 21
STING manifests self DNA-dependent inflammatory disease
journal, November 2012
- Ahn, J.; Gutman, D.; Saijo, S.
- Proceedings of the National Academy of Sciences, Vol. 109, Issue 47
Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases
journal, September 2015
- Gao, Daxing; Li, Tuo; Li, Xiao-Dong
- Proceedings of the National Academy of Sciences, Vol. 112, Issue 42
cGAS is essential for cellular senescence
journal, May 2017
- Yang, Hui; Wang, Hanze; Ren, Junyao
- Proceedings of the National Academy of Sciences, Vol. 114, Issue 23
High-Throughput Screening with Quantitation of ATP Consumption: A Universal Non-Radioisotope, Homogeneous Assay for Protein Kinase
journal, April 2004
- Koresawa, Mitsunori; Okabe, Takayoshi
- ASSAY and Drug Development Technologies, Vol. 2, Issue 2
Phaser crystallographic software
journal, July 2007
- McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D.
- Journal of Applied Crystallography, Vol. 40, Issue 4
Features and development of Coot
journal, March 2010
- Emsley, P.; Lohkamp, B.; Scott, W. G.
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4
Cyclic GMP-AMP Is an Endogenous Second Messenger in Innate Immune Signaling by Cytosolic DNA
journal, December 2012
- Wu, J.; Sun, L.; Chen, X.
- Science, Vol. 339, Issue 6121
Cyclic GMP-AMP Synthase Is a Cytosolic DNA Sensor That Activates the Type I Interferon Pathway
journal, December 2012
- Sun, L.; Wu, J.; Du, F.
- Science, Vol. 339, Issue 6121
Cyclic GMP-AMP Synthase Is an Innate Immune Sensor of HIV and Other Retroviruses
journal, August 2013
- Gao, D.; Wu, J.; Wu, Y. -T.
- Science, Vol. 341, Issue 6148
Pathogen Recognition and Inflammatory Signaling in Innate Immune Defenses
journal, April 2009
- Mogensen, T. H.
- Clinical Microbiology Reviews, Vol. 22, Issue 2
Nucleic Acid Recognition by the Innate Immune System
journal, April 2011
- Barbalat, Roman; Ewald, Sarah E.; Mouchess, Maria L.
- Annual Review of Immunology, Vol. 29, Issue 1
Discovery of PF-06928215 as a high affinity inhibitor of cGAS enabled by a novel fluorescence polarization assay
journal, September 2017
- Hall, Justin; Brault, Amy; Vincent, Fabien
- PLOS ONE, Vol. 12, Issue 9
PHENIX: a comprehensive Python-based system for macromolecular structure solution.
text, January 2010
- Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
- Apollo - University of Cambridge Repository
Cutting Edge: Antimalarial Drugs Inhibit IFN-β Production through Blockade of Cyclic GMP-AMP Synthase–DNA Interaction
journal, March 2015
- An, Jie; Woodward, Joshua J.; Sasaki, Tomikazu
- The Journal of Immunology, Vol. 194, Issue 9
Cutting Edge: cGAS Is Required for Lethal Autoimmune Disease in the Trex1-Deficient Mouse Model of Aicardi–Goutières Syndrome
journal, July 2015
- Gray, Elizabeth E.; Treuting, Piper M.; Woodward, Joshua J.
- The Journal of Immunology, Vol. 195, Issue 5
Works referencing / citing this record:
Pharmacological modulation of nucleic acid sensors — therapeutic potential and persisting obstacles
journal, September 2019
- Vanpouille-Box, Claire; Hoffmann, Jules A.; Galluzzi, Lorenzo
- Nature Reviews Drug Discovery, Vol. 18, Issue 11
Regulation of cGAS- and RLR-mediated immunity to nucleic acids
journal, December 2019
- Ablasser, Andrea; Hur, Sun
- Nature Immunology, Vol. 21, Issue 1
Interrupting cyclic dinucleotide-cGAS–STING axis with small molecules
journal, January 2019
- Sintim, Herman O.; Mikek, Clinton G.; Wang, Modi
- MedChemComm, Vol. 10, Issue 12
Human cGAS catalytic domain has an additional DNA-binding interface that enhances enzymatic activity and liquid-phase condensation
journal, May 2019
- Xie, Wei; Lama, Lodoe; Adura, Carolina
- Proceedings of the National Academy of Sciences
Novel and emerging treatments for Aicardi-Goutières syndrome
journal, January 2020
- Tonduti, Davide; Fazzi, Elisa; Badolato, Raffaele
- Expert Review of Clinical Immunology, Vol. 16, Issue 2
MALDI-TOF Mass Spectrometry-Based High-Throughput Screening for Inhibitors of the Cytosolic DNA Sensor cGAS
journal, October 2019
- Simon, Roman P.; Winter, Martin; Kleiner, Carola
- SLAS DISCOVERY: Advancing the Science of Drug Discovery, Vol. 25, Issue 4