title: Cutting edge: Antimalarial drugs inhibit IFN-β production through blockade of cyclic GMP-AMP synthase-DNA interaction.
abstract: Type I IFN is strongly implicated in the pathogenesis of systemic autoimmune diseases, such as lupus, and rare monogenic IFNopathies, including Aicardi-Goutières syndrome. Recently, a new DNA-activated pathway involving the enzyme cyclic GMP-AMP synthase (cGAS) was described and potentially linked to Aicardi-Goutières syndrome. To identify drugs that could potentially inhibit cGAS activity, we performed in silico screening of drug libraries. By computational analysis, we identified several antimalarial drugs (AMDs) that were predicted to interact with the cGAS/dsDNA complex. Our studies validated that several AMDs were effective inhibitors of IFN-β production and that they functioned by inhibiting dsDNA stimulation of cGAS. Because AMDs have been widely used in human diseases and have an excellent safety profile, our findings suggest new therapeutic strategies for the treatment of severe debilitating diseases associated with type I IFNs due to cGAS activation.
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA 98109;
authors.forename: Jie
authors.initials: J
authors.lastname: An
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA 98195;
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Woodward
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA 98195;
authors.forename: Tomikazu
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA 98195; Department of Bioengineering, University of Washington, Seattle, WA 98195; and.
authors.forename: Mark
authors.initials: M
authors.lastname: Minie
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA 98109; Department of Immunology, University of Washington, Seattle, WA 98109 elkon@uw.edu.
authors.forename: Keith B
authors.initials: KB
authors.lastname: Elkon
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D002460:Cell Line; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D016899:Interferon-beta / Q000096:biosynthesis*; D008958:Models, Molecular; D009713:Nucleotidyltransferases / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D013329:Structure-Activity Relationship; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D000962:Antimalarials; D004247:DNA; D016899:Interferon-beta; D009713:Nucleotidyltransferases; C578390:cGAS protein, human; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase