Small molecule inhibition of cGAS reduces interferon expression in primary macrophages from autoimmune mice Journal Article
| Authors: | Vincent, J.; Adura, C.; Gao, P.; Luz, A.; Lama, L.; Asano, Y.; Okamoto, R.; Imaeda, T.; Aida, J.; Rothamel, K.; Gogakos, T.; Steinberg, J.; Reasoner, S.; Aso, K.; Tuschl, T.; Patel, D. J.; Glickman, J. F.; Ascano, M. |
| Article Title: | Small molecule inhibition of cGAS reduces interferon expression in primary macrophages from autoimmune mice |
| Abstract: | Cyclic GMP-AMP synthase is essential for innate immunity against infection and cellular damage, serving as a sensor of DNA from pathogens or mislocalized self-DNA. Upon binding double-stranded DNA, cyclic GMP-AMP synthase synthesizes a cyclic dinucleotide that initiates an inflammatory cellular response. Mouse studies that recapitulate causative mutations in the autoimmune disease Aicardi-Goutières syndrome demonstrate that ablating the cyclic GMP-AMP synthase gene abolishes the deleterious phenotype. Here, we report the discovery of a class of cyclic GMP-AMP synthase inhibitors identified by a high-throughput screen. These compounds possess defined structure-activity relationships and we present crystal structures of cyclic GMP-AMP synthase, double-stranded DNA, and inhibitors within the enzymatic active site. We find that a chemically improved member, RU.521, is active and selective in cellular assays of cyclic GMP-AMP synthase-mediated signaling and reduces constitutive expression of interferon in macrophages from a mouse model of Aicardi-Goutières syndrome. RU.521 will be useful toward understanding the biological roles of cyclic GMP-AMP synthase and can serve as a molecular scaffold for development of future autoimmune therapies. © 2017 The Author(s). |
| Keywords: | mus |
| Journal Title: | Nature Communications |
| Volume: | 8 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2017-09-29 |
| Start Page: | 750 |
| Language: | English |
| DOI: | 10.1038/s41467-017-00833-9 |
| PROVIDER: | scopus |
| PMCID: | PMC5622107 |
| PUBMED: | 28963528 |
| DOI/URL: | |
| Notes: | Article -- Correction issued, see DOI: 10.1038/s41467-017-01770-3 -- Export Date: 2 November 2017 -- Source: Scopus |
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