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

Nat Commun. 2019 May 21;10(1):2261. doi: 10.1038/s41467-019-08620-4.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoimmune Diseases / drug therapy
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / pathology
  • Cells, Cultured
  • Crystallography, X-Ray
  • DNA / immunology
  • DNA / metabolism
  • Drug Discovery / methods*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • High-Throughput Screening Assays / methods
  • Humans
  • Immunity, Innate / drug effects
  • Interferons / immunology
  • Interferons / metabolism
  • Macrophages
  • Models, Molecular
  • Nucleotides, Cyclic / immunology
  • Nucleotides, Cyclic / metabolism
  • Nucleotidyltransferases / antagonists & inhibitors*
  • Nucleotidyltransferases / immunology
  • Nucleotidyltransferases / isolation & purification
  • Nucleotidyltransferases / metabolism
  • Primary Cell Culture
  • Recombinant Proteins / immunology
  • Recombinant Proteins / isolation & purification
  • Recombinant Proteins / metabolism

Substances

  • Enzyme Inhibitors
  • Nucleotides, Cyclic
  • Recombinant Proteins
  • cyclic guanosine monophosphate-adenosine monophosphate
  • DNA
  • Interferons
  • MB21D1 protein, human
  • Nucleotidyltransferases