Cutting Edge: Antimalarial Drugs Inhibit IFN-β Production through Blockade of Cyclic GMP-AMP Synthase-DNA Interaction

被引：186

作者：

An, Jie ^{[1
]}

Woodward, Joshua J. ^{[2
]}

Sasaki, Tomikazu ^{[3
]}

Minie, Mark ^{[2
,4
]}

Elkon, Keith B. ^{[1
,5
]}

机构：

[1] Univ Washington, Dept Med, Div Rheumatol, Seattle, WA 98109 USA

[2] Univ Washington, Dept Microbiol, Seattle, WA 98195 USA

[3] Univ Washington, Dept Chem, Seattle, WA 98195 USA

[4] Univ Washington, Dept Bioengn, Seattle, WA 98195 USA

[5] Univ Washington, Dept Immunol, Seattle, WA 98109 USA

来源：

JOURNAL OF IMMUNOLOGY | 2015年 / 194卷 / 09期

关键词：

SYSTEMIC-LUPUS-ERYTHEMATOSUS; AICARDI-GOUTIERES-SYNDROME; CYTOSOLIC DNA; EXONUCLEASE TREX1; INTERFERON-ALPHA; DEPENDENT MANNER; GENE; CGAS; MUTATIONS; INDUCTION;

D O I：

10.4049/jimmunol.1402793

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Type I IFN is strongly implicated in the pathogenesis of systemic autoimmune diseases, such as lupus, and rare monogenic IFNopathies, including Aicardi-Goutieres syndrome. Recently, a new DNA-activated pathway involving the enzyme cyclic GMP-AMP synthase (cGAS) was described and potentially linked to Aicardi-Goutieres 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-beta 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.

引用

页码：4089 / 4093

页数：5

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