STING inhibitors target the cyclic dinucleotide binding pocket

Abstract

Cytosolic DNA activates cGAS (cytosolic DNA sensor cyclic AMP-GMP synthase)-STING (stimulator of interferon genes) signaling, which triggers interferon and inflammatory responses that help defend against microbial infection and cancer. However, aberrant cytosolic self-DNA in Aicardi–Goutière’s syndrome and constituently active gain-of-function mutations in STING in STING-associated vasculopathy with onset in infancy (SAVI) patients lead to excessive type I interferons and proinflammatory cytokines, which cause difficult-to-treat and sometimes fatal autoimmune disease. Here, in silico docking identified a potent STING antagonist SN-011 that binds with higher affinity to the cyclic dinucleotide (CDN)-binding pocket of STING than endogenous 2′3′-cGAMP. SN-011 locks STING in an open inactive conformation, which inhibits interferon and inflammatory cytokine induction activated by 2′3′-cGAMP, herpes simplex virus type 1 infection, Trex1 deficiency, overexpression of cGAS-STING, or SAVI STING mutants. In Trex1−/− mice, SN-011 was well tolerated, strongly inhibited hallmarks of inflammation and autoimmunity disease, and prevented death. Thus, a specific STING inhibitor that binds to the STING CDN-binding pocket is a promising lead compound for STING-driven disease.

Dysfunctional telomeres through mitostress‐induced cGAS/STING activation to aggravate immune senescence and viral pneumonia

“…Interestingly, a recent study showed that bats harbored a non-functional STING gene, which allowed them to withstand tissue stress and SARS-CoV-2 infection without ill effects (Gorbunova et al, 2020). Inspired by these findings, scientists endeavor to develop the therapeutics aimed to improve mitochondrial integrity or block the STING pathway in treating inflammatory diseases (Hong et al, 2021).…”

“…Macrophage-targeted senotherapeutics is currently underway to treat age-related disorders including critical respiratory infection (Pham et al, 2021). Another rationale for the macrophage-centered study is the so called "trained immunity", a non-specific but stable immunological memory formed by innate immune cells after initial infection (You et al, 2021). Emerging evidences have shown that early infections, through metabolic-epigenetic rewiring, shape long-lasting immunological imprinter in innate immune cells, which endows the immune cells such as macrophages to rapidly and highly respond to re-infection, and may simultaneously induce the aggravated inflammatory response.…”

STING Agonists/Antagonists: Their Potential as Therapeutics and Future Developments

“…These compounds have, nevertheless, generated significant interest from pharmaceutical companies, and it is expected that joint efforts will soon identify candidates for early clinical exploration. Just recently, Hong and colleagues [ 74 ] identified a class of STING inhibitors capable of competing for the binding of cGAMP to STING. The effort, led by Chinese academic institutions, started from in silico modeling, complemented by the screening of chemical libraries for binders to the soluble cyclic-dinucleotide binding domain of STING.…”

“…One of these compounds, named SN-11, showed activity in vivo, with comparable efficacy to the covalent STING antagonist C-176. As for C-176, SN-11 showed good efficacy in the Trex1 KO model [ 74 ].…”

Intervention of cGAS‒STING signaling in sterile inflammatory diseases

“…Interestingly, astin C specifically blocks the recruitment of IRF3 onto the STING signalosome while keeping the STING‒TBK1 interaction intact. Recently, an in silico docking screen against a STING CDN-binding pocket led to the discovery of SN-011 as a novel STING antagonist with promising therapeutic potential ( Hong et al., 2021b ). SN-011 significantly reduces IFN and inflammatory cytokine induction activated by 2′3′-cGAMP, Trex1 deficiency, or SAVI-associated STING mutants.…”