Compound C Reducing Interferon Expression by Inhibiting cGAMP Accumulation

Cyclic GMP-AMP (cGAMP) synthase (cGAS) is a major DNA sensor responsible for cytosolic DNA-mediated innate immune response. Inhibition of cGAS may be an effective strategy for treating autoimmune diseases such as Aicardi-Goutieres syndrome and systemic lupus erythematosus. Compound C (also known as...

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Bibliographic Details
Published in:Frontiers in pharmacology 2020-02, Vol.11, p.88
Main Authors: Lai, Junzhong, Luo, Xuan, Tian, Shuoran, Zhang, Xing, Huang, Shanlu, Wang, Hanze, Li, Qiumei, Cai, Shaoli, Chen, Qi
Format: Article
Language:English
Subjects:
cGAMP
cGAS
compound C
DNA sensing
dorsomorphin
Pharmacology
type I interferon
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Summary:Cyclic GMP-AMP (cGAMP) synthase (cGAS) is a major DNA sensor responsible for cytosolic DNA-mediated innate immune response. Inhibition of cGAS may be an effective strategy for treating autoimmune diseases such as Aicardi-Goutieres syndrome and systemic lupus erythematosus. Compound C (also known as Dorsomorphin) has been annotated as a potent and reversible inhibitor for AMPKs as well as ALK protein kinases. Here, we report a new function of Compound C which can suppress dsDNA-dependent type I interferon induction. These effects were not dependent on the activities of AMPK proteins. o assays and liquid chromatograph-mass spectrometry data show that Compound C has the capability of reducing cGAMP accumulation, suggesting that Compound C may function as a modulator involved in the cGAS-STING-mediated DNA sensing pathway. Furthermore, Compound C is able to rescue the autoimmune phenotypes in a mouse model carrying the Trex1 gene deficiency. These data demonstrate a new and inverse correlation between Compound C and type I interferon production in response to dsDNA signaling.
ISSN:1663-9812
1663-9812
DOI:10.3389/fphar.2020.00088