Inhibition of STING Signaling with Flavonoid Compounds

T R Ullah^{1, 2}, RL Ambrose^{1, 2}, O Laczka³, KR Balka^{4, 5, 6}, D De Nardo^{4, 5, 6}, MP Gantier^{1, 2}

1. Molecular and translational Science, Monash University

2. Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria

3. Noxopharm Limited , Gordon NSW 2072 Australia, Sydney

4. Department of Anatomy and Developmental Biology , Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria

5. Department of Medical Biology, The University of Melbourne

6. The Walter and Eliza Hall Institute of Medical Research, Inflammation division, Parkville, Victoria, Australia

Abstract Content

The cGAS-STING pathway plays a major role in aberrant immune responses seen in autoinflammatory diseases including interferonopathies such as the Aicardi-Goutieres syndrome. Critically, this pathway can be amplified through the propagation of cyclic GMP-AMP (cGAMP), the product of cGAS, between cell: cell interactions, known as gap junctions. Flavonoid compounds have been suggested to impact the activity of gap junction, but whether this can alter propagation of cGAS-STING signalling is not known. In co-cultures of cGAMP donor cells with STING expressing recipient cells, Genistein was the only flavonoid tested to decrease adjacent cell transactivation. This effect was concurrent with a decreased gap junction intercellular communication. Critically, Genistein pre-treatment of STING expressing recipient cells abolished cellular transactivation, indicating a direct effect on STING signalling. Accordingly, Genistein significantly decreased STING signalling and its antiviral effect against Semliki Forest Virus, upon activation by its agonist. Short pre-treatment with Genistein impacted STING phosphorylation, along with that of IRF3 and IKKe, confirming a direct effect on STING signalling. Further, Idronoxil, a synthetic variant of Genistein with great safety profile in clinical trials over >800 patients, was a >30 fold more potent inhibitor of STING signalling than Genistein.

These findings establish a converging inhibitory activity of Genistein on cGAS-STING signalling, acting on preventing cGAMP transfer between adjacent cells, and preventing STING activation. In addition, select flavonoid compounds such as Idronoxil may present novel therapeutic opportunities to inhibit the cGAS-STING pathway involved in a growing number of auto-inflammatory diseases.