Development of human cGAS-specific small-molecule inhibitors for repression of dsDNA-triggered interferon expression

作者：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 · 发表于：Nature Communications · 年份：2019 · DOI：10.1038/s41467-019-08620-4 · 被引用次数：297 · 研究领域：interferon and immune responses、Immune Response and Inflammation、Immune Cell Function and Interaction

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.