publication . Article . Other literature type . 2017

Small molecule inhibition of cGAS reduces interferon expression in primary macrophages from autoimmune mice.

Tasos Gogakos; Tasos Gogakos; J. Fraser Glickman; Antonio Luz; Antonio Luz; Thomas Tuschl; Thomas Tuschl; Jessica Vincent; Rei Okamoto; Jumpei Aida; ...
Open Access English
  • Published: 29 Sep 2017 Journal: Nature Communications, volume 8 (eissn: 2041-1723, Copyright policy)
  • Publisher: Nature Publishing Group UK
Abstract
Upon DNA binding cyclic GMP-AMP synthase (cGAS) produces a cyclic dinucleotide, which leads to the upregulation of inflammatory genes. Here the authors develop small molecule cGAS inhibitors, functionally characterize them and present the inhibitor and DNA bound cGAS crystal structures, which will facilitate drug development.
Subjects
free text keywords: Article, Science, Q, General Biochemistry, Genetics and Molecular Biology, General Physics and Astronomy, General Chemistry, Innate immune system, DNA, chemistry.chemical_compound, chemistry, Biology, Interferon, medicine.drug, medicine, Small molecule, Enzyme, chemistry.chemical_classification, Biochemistry, Downregulation and upregulation, Gene, ATP synthase, biology.protein
Funded by
NIH| NE-CAT Center for Advanced Macromolecular Crystallography
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 4P41GM103403-14
  • Funding stream: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
,
NIH| Chemistry Biology Interface Training Grant
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 4T32GM065086-14
  • Funding stream: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
,
NIH| Deciphering Post-transcriptional gene regulatory networks in cellular stress and innate immunity
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 1R35GM119569-01
  • Funding stream: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
,
NIH| MOUSE GENETICS
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 2P30CA008748-43
  • Funding stream: NATIONAL CANCER INSTITUTE
,
NIH| Posttranscriptional regulation by mRNA-binding shuttling and transport proteins
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5R01GM104962-02
  • Funding stream: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
61 references, page 1 of 5

Wu, J, Chen, ZJ. Innate immune sensing and signaling of cytosolic nucleic acids. Annu. Rev. Immunol.. 2014; 32: 461-488 [OpenAIRE] [PubMed] [DOI]

Barbalat, R, Ewald, SE, Mouchess, ML, Barton, GM. Nucleic acid recognition by the innate immune system. Annu. Rev. Immunol.. 2011; 29: 185-214 [OpenAIRE] [PubMed] [DOI]

Barrat, FJ, Elkon, KB, Fitzgerald, KA. Importance of Nucleic Acid Recognition in Inflammation and Autoimmunity. Annu. Rev. Med.. 2015; 67: 052814-023338

4.Christensen, M. H.. & Paludan, S. R. Viral evasion of DNA-stimulated innate immune responses. Cell Mol. Immunol. doi:10.1038/cmi.2016.06 (2016).

Dempsey, A, Bowie, AG. Innate immune recognition of DNA: A recent history. Virology. 2015; 479–480: 146-152 [OpenAIRE] [PubMed] [DOI]

Sun, L, Wu, J, Du, F, Chen, X, Chen, ZJ. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science (New York, NY). 2013; 339: 786-791 [OpenAIRE] [DOI]

Schoggins, JW. A diverse range of gene products are effectors of the type I interferon antiviral response. Nature. 2011; 472: 481-485 [OpenAIRE] [PubMed] [DOI]

Cai, X, Chiu, Y-H, Chen, ZJ. The cGAS-cGAMP-STING pathway of cytosolic DNA sensing and signaling. Mol. Cell. 2014; 54: 289-296 [OpenAIRE] [PubMed] [DOI]

Hornung, V, Hartmann, R, Ablasser, A, Hopfner, K-P. OAS proteins and cGAS: unifyingconcepts in sensing and respondingto cytosolic nucleic acids. Nat. Rev. Immunol.. 2014; 14: 521-528 [OpenAIRE] [PubMed] [DOI]

Bhat, N, Fitzgerald, KA. Recognition of cytosolic DNA by cGAS and other STING-dependent sensors. Eur. J. Immunol.. 2014; 44: 634-640 [OpenAIRE] [PubMed] [DOI]

Wu, J. Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science (New York, NY). 2013; 339: 826-830 [OpenAIRE] [DOI]

Diner, EJ. The innate immune DNA sensor cGAS produces a noncanonical cyclic dinucleotide that activates human STING. Cell Rep.. 2013; 3: 1355-1361 [OpenAIRE] [PubMed] [DOI]

Ablasser, A. cGAS produces a 2‘-5’-linked cyclic dinucleotide second messenger that activates STING. Nature. 2013; 498: 380-384 [OpenAIRE] [PubMed] [DOI]

Gao, P. Cyclic [G(2’,5’)pA(3‘,5’)p] is the metazoan second messenger produced by DNA-activated cyclic GMP-AMP synthase. Cell. 2013; 153: 1094-1107 [OpenAIRE] [PubMed] [DOI]

Zhang, X. Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING. Mol. Cell. 2013; 51: 226-235 [OpenAIRE] [PubMed] [DOI]

61 references, page 1 of 5
Abstract
Upon DNA binding cyclic GMP-AMP synthase (cGAS) produces a cyclic dinucleotide, which leads to the upregulation of inflammatory genes. Here the authors develop small molecule cGAS inhibitors, functionally characterize them and present the inhibitor and DNA bound cGAS crystal structures, which will facilitate drug development.
Subjects
free text keywords: Article, Science, Q, General Biochemistry, Genetics and Molecular Biology, General Physics and Astronomy, General Chemistry, Innate immune system, DNA, chemistry.chemical_compound, chemistry, Biology, Interferon, medicine.drug, medicine, Small molecule, Enzyme, chemistry.chemical_classification, Biochemistry, Downregulation and upregulation, Gene, ATP synthase, biology.protein
Funded by
NIH| NE-CAT Center for Advanced Macromolecular Crystallography
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 4P41GM103403-14
  • Funding stream: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
,
NIH| Chemistry Biology Interface Training Grant
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 4T32GM065086-14
  • Funding stream: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
,
NIH| Deciphering Post-transcriptional gene regulatory networks in cellular stress and innate immunity
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 1R35GM119569-01
  • Funding stream: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
,
NIH| MOUSE GENETICS
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 2P30CA008748-43
  • Funding stream: NATIONAL CANCER INSTITUTE
,
NIH| Posttranscriptional regulation by mRNA-binding shuttling and transport proteins
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5R01GM104962-02
  • Funding stream: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
61 references, page 1 of 5

Wu, J, Chen, ZJ. Innate immune sensing and signaling of cytosolic nucleic acids. Annu. Rev. Immunol.. 2014; 32: 461-488 [OpenAIRE] [PubMed] [DOI]

Barbalat, R, Ewald, SE, Mouchess, ML, Barton, GM. Nucleic acid recognition by the innate immune system. Annu. Rev. Immunol.. 2011; 29: 185-214 [OpenAIRE] [PubMed] [DOI]

Barrat, FJ, Elkon, KB, Fitzgerald, KA. Importance of Nucleic Acid Recognition in Inflammation and Autoimmunity. Annu. Rev. Med.. 2015; 67: 052814-023338

4.Christensen, M. H.. & Paludan, S. R. Viral evasion of DNA-stimulated innate immune responses. Cell Mol. Immunol. doi:10.1038/cmi.2016.06 (2016).

Dempsey, A, Bowie, AG. Innate immune recognition of DNA: A recent history. Virology. 2015; 479–480: 146-152 [OpenAIRE] [PubMed] [DOI]

Sun, L, Wu, J, Du, F, Chen, X, Chen, ZJ. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science (New York, NY). 2013; 339: 786-791 [OpenAIRE] [DOI]

Schoggins, JW. A diverse range of gene products are effectors of the type I interferon antiviral response. Nature. 2011; 472: 481-485 [OpenAIRE] [PubMed] [DOI]

Cai, X, Chiu, Y-H, Chen, ZJ. The cGAS-cGAMP-STING pathway of cytosolic DNA sensing and signaling. Mol. Cell. 2014; 54: 289-296 [OpenAIRE] [PubMed] [DOI]

Hornung, V, Hartmann, R, Ablasser, A, Hopfner, K-P. OAS proteins and cGAS: unifyingconcepts in sensing and respondingto cytosolic nucleic acids. Nat. Rev. Immunol.. 2014; 14: 521-528 [OpenAIRE] [PubMed] [DOI]

Bhat, N, Fitzgerald, KA. Recognition of cytosolic DNA by cGAS and other STING-dependent sensors. Eur. J. Immunol.. 2014; 44: 634-640 [OpenAIRE] [PubMed] [DOI]

Wu, J. Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science (New York, NY). 2013; 339: 826-830 [OpenAIRE] [DOI]

Diner, EJ. The innate immune DNA sensor cGAS produces a noncanonical cyclic dinucleotide that activates human STING. Cell Rep.. 2013; 3: 1355-1361 [OpenAIRE] [PubMed] [DOI]

Ablasser, A. cGAS produces a 2‘-5’-linked cyclic dinucleotide second messenger that activates STING. Nature. 2013; 498: 380-384 [OpenAIRE] [PubMed] [DOI]

Gao, P. Cyclic [G(2’,5’)pA(3‘,5’)p] is the metazoan second messenger produced by DNA-activated cyclic GMP-AMP synthase. Cell. 2013; 153: 1094-1107 [OpenAIRE] [PubMed] [DOI]

Zhang, X. Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING. Mol. Cell. 2013; 51: 226-235 [OpenAIRE] [PubMed] [DOI]

61 references, page 1 of 5
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