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Inhibition of Cyclic GMP ‐ AMP Synthase Using a Novel Antimalarial Drug Derivative in Trex1 ‐Deficient Mice
Author(s) -
An Jie,
Woodward Joshua J.,
Lai Weinan,
Minie Mark,
Sun Xizhang,
Tanaka Lena,
Snyder Jessica M.,
Sasaki Tomikazu,
Elkon Keith B.
Publication year - 2018
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.40559
Subject(s) - isg15 , in vitro , biology , interferon , hydroxychloroquine , pathogenesis , real time polymerase chain reaction , pharmacology , microbiology and biotechnology , chemistry , gene , biochemistry , immunology , medicine , disease , ubiquitin , covid-19 , infectious disease (medical specialty)
Objective Type I interferon ( IFN ) is strongly implicated in the pathogenesis of systemic lupus erythematosus ( SLE ) as well as rare monogenic interferonopathies such as Aicardi‐Goutières syndrome ( AGS ), a disease attributed to mutations in the DNA exonuclease TREX 1 . The DNA ‐activated type I IFN pathway cyclic GMP ‐ AMP ( cGAMP ) synthase ( cGAS ) is linked to subsets of AGS and lupus. This study was undertaken to identify inhibitors of the DNA – cGAS interaction, and to test the lead candidate drug, X6, in a mouse model of AGS. Methods Trex1 −/− mice were treated orally from birth with either X6 or hydroxychloroquine ( HCQ ) for 8 weeks. Expression of IFN ‐stimulated genes ( ISG s) was quantified by quantitative polymerase chain reaction. Multiple reaction monitoring by ultra‐performance liquid chromatography coupled with tandem mass spectrometry was used to quantify the production of cGAMP and X6 drug concentrations in the serum and heart tissue of Trex1 −/− mice. Results On the basis of the efficacy‐to‐toxicity ratio established in vitro, drug X6 was selected as the lead candidate for treatment of Trex1 −/− mice. X6 was significantly more effective than HCQ in attenuating ISG expression in mouse spleens ( P < 0.01 for Isg15 and Isg20 ) and hearts ( P < 0.05 for Isg15 , Mx1 , and Ifnb, and P < 0.01 for Cxcl10 ), and in reducing the production of cGAMP in mouse heart tissue ( P < 0.05), thus demonstrating target engagement by the X6 compound. Of note, X6 was also more effective than HCQ in reducing ISG expression in vitro ( P < 0.05 for IFI 27 and MX 1 , and P < 0.01 for IFI 44L and PKR ) in human peripheral blood mononuclear cells from patients with SLE . Conclusion This study demonstrates that X6 is superior to HCQ for the treatment of an experimental autoimmune myocarditis mediated in vivo by the cGAS /stimulator of IFN genes ( cGAS / STING ) pathway. The findings suggest that drug X6 could be developed as a novel treatment for AGS and/or lupus to inhibit activation of the cGAS / STING pathway.