| Autor: |
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 |
| Předmět: |
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| Zdroj: |
Nature Communications; 9/29/2017, Vol. 8 Issue 1, p1-13, 13p |
| Abstrakt: |
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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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