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- Title
Small molecule inhibition of cGAS reduces interferon expression in primary macrophages from autoimmune mice.
- Authors
Vincent, Jessica; Adura, Carolina; Pu Gao; Luz, Antonio; Lama, Lodoe; Yasutomi Asano; Rei Okamoto; Toshihiro Imaeda; Aida, Jumpei; Rothamel, Katherine; Gogakos, Tasos; Steinberg, Joshua; Reasoner, Seth; Kazuyoshi Aso; Tuschl, Thomas; Patel, Dinshaw J.; Glickman, J. Fraser; Ascano, Manuel
- 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.
- Subjects
SMALL molecules; INTERFERONS; MACROPHAGES; STRUCTURE-activity relationships; DISEASE resistance of plants; TYPE I interferons; DNA structure; ACETOLACTATE synthase
- Publication
Nature Communications, 2017, Vol 8, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-017-00833-9