Development of human cGAS-specific small-molecule inhibitors for repression of dsDNA-triggered interferon expression Article Swipe
Lodoe Lama
,
Carolina Adura
,
Wei Xie
,
Daisuke Tomita
,
Taku Kamei
,
Vitaly Kuryavyi
,
Tasos Gogakos
,
Joshua Steinberg
,
Michael Miller
,
Lavoisier Ramos‐Espiritu
,
Yasutomi Asano
,
Shogo Hashizume
,
Jumpei Aida
,
Toshihiro Imaeda
,
Rei Okamoto
,
Andy Jennings
,
Mayako Michino
,
Takanobu Kuroita
,
Andrew W. Stamford
,
Pu Gao
,
Peter T. Meinke
,
J. Fraser Glickman
,
Dinshaw J. Patel
,
Thomas Tuschl
·
YOU?
·
· 2019
· Open Access
·
· DOI: https://doi.org/10.1038/s41467-019-08620-4
YOU?
·
· 2019
· Open Access
·
· DOI: https://doi.org/10.1038/s41467-019-08620-4
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.
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Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1038/s41467-019-08620-4
- https://www.nature.com/articles/s41467-019-08620-4.pdf
- OA Status
- gold
- Cited By
- 244
- References
- 49
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W2945498322
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
-
https://openalex.org/W2945498322Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1038/s41467-019-08620-4Digital Object Identifier
- Title
-
Development of human cGAS-specific small-molecule inhibitors for repression of dsDNA-triggered interferon expressionWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2019Year of publication
- Publication date
-
2019-05-21Full publication date if available
- Authors
-
Lodoe Lama, Carolina Adura, Wei Xie, Daisuke Tomita, Taku Kamei, Vitaly Kuryavyi, Tasos Gogakos, Joshua Steinberg, Michael Miller, Lavoisier Ramos‐Espiritu, Yasutomi Asano, Shogo Hashizume, Jumpei Aida, Toshihiro Imaeda, Rei Okamoto, Andy Jennings, Mayako Michino, Takanobu Kuroita, Andrew W. Stamford, Pu Gao, Peter T. Meinke, J. Fraser Glickman, Dinshaw J. Patel, Thomas TuschlList of authors in order
- Landing page
-
https://doi.org/10.1038/s41467-019-08620-4Publisher landing page
- PDF URL
-
https://www.nature.com/articles/s41467-019-08620-4.pdfDirect link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
goldOpen access status per OpenAlex
- OA URL
-
https://www.nature.com/articles/s41467-019-08620-4.pdfDirect OA link when available
- Concepts
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Innate immune system, Small molecule, Drug discovery, Interferon, Cell biology, Intracellular, High-throughput screening, Chemistry, ATP synthase, Biology, Immune system, Enzyme, Biochemistry, ImmunologyTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
244Total citation count in OpenAlex
- Citations by year (recent)
-
2025: 48, 2024: 61, 2023: 45, 2022: 33, 2021: 24Per-year citation counts (last 5 years)
- References (count)
-
49Number of works referenced by this work
- Related works (count)
-
10Other works algorithmically related by OpenAlex
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