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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Autoimmune Diseases / drug therapy
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Autoimmune Diseases / immunology
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Autoimmune Diseases / pathology
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Cells, Cultured
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Crystallography, X-Ray
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DNA / immunology
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DNA / metabolism
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Drug Discovery / methods*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Enzyme Inhibitors / therapeutic use
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High-Throughput Screening Assays / methods
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Humans
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Immunity, Innate / drug effects
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Interferons / immunology
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Interferons / metabolism
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Macrophages
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Models, Molecular
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Nucleotides, Cyclic / immunology
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Nucleotides, Cyclic / metabolism
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Nucleotidyltransferases / antagonists & inhibitors*
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Nucleotidyltransferases / immunology
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Nucleotidyltransferases / isolation & purification
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Nucleotidyltransferases / metabolism
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Primary Cell Culture
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Recombinant Proteins / immunology
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Recombinant Proteins / isolation & purification
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Recombinant Proteins / metabolism
Substances
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Enzyme Inhibitors
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Nucleotides, Cyclic
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Recombinant Proteins
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cyclic guanosine monophosphate-adenosine monophosphate
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DNA
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Interferons
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Nucleotidyltransferases
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cGAS protein, human