Download MendeleyDevelopment of human cGAS-specific small-molecule inhibitors for repression of dsDNA-triggered interferon expression.
Lama, L., Adura, C., Xie, W., Tomita, D., Kamei, T., Kuryavyi, V., Gogakos, T., Steinberg, J.I., Miller, M., Ramos-Espiritu, L., Asano, Y., Hashizume, S., Aida, J., Imaeda, T., Okamoto, R., Jennings, A.J., Michino, M., Kuroita, T., Stamford, A., Gao, P., Meinke, P., Glickman, J.F., Patel, D.J., Tuschl, T.(2019) Nat Commun 10: 2261-2261
- PubMed: 31113940
- DOI: https://doi.org/10.1038/s41467-019-08620-4
- Primary Citation of Related Structures:
6MJU, 6MJW, 6MJX - PubMed Abstract:
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.
Organizational Affiliation:
Laboratory for RNA Molecular Biology, The Rockefeller University, 1230 York Ave, Box 186, New York, NY, 10065, USA.
