Article type:
Research
Estimated read time:
3 mins min read
Published:
26/09/2025
Using a small-molecule drug to interfere with the joining together of Stimulator of Interferon Genes (STING) protein molecules and inhibit their activation
Date of publication:
14/3/26
Author:
Roger Brooks
Category:
Therapeutics
Article body content:
Plain Language
The immune system has a sensor called STING, which helps the body respond to viruses and damaged DNA. However, in some rare genetic diseases like STING-associated vasculopathy with onset in infancy SAVI and Aicardi-Goutières syndrome, STING becomes overactive and causes harmful inflammation.
In this study, researchers identified a small molecule drug (BB-Cl-amidine) that blocks STING activation.
They found that:
· The drug stops STING from forming clusters (oligomers), which are required for it to signal, by modifying a part of the molecule called cysteine at position 148 (Cys148).
· It reduces production of interferon and inflammatory cytokines.
· In a mouse model of STING-driven disease, the drug reduced heart inflammation and improved survival.
This study provides proof that STING itself can be directly targeted with drugs, offering hope for more precise treatments for STING-related diseases.
Why it Matters
This study:
· Identifies a direct STING oligomerization inhibitor
· Demonstrates a new therapeutic mechanism distinct from palmitoylation inhibition
· Validates Cys148 as a druggable regulatory residue
· Provides proof-of-concept for targeting STING in interferon-driven diseases
It expands the pharmacological toolkit for treating STING-mediated autoinflammation.
Hope for the Future
This work:
· Establishes oligomerization blockade as a therapeutic strategy
· Suggests potential for precision inhibitors in SAVI and Aicardi–Goutières syndrome (AGS)
· Provides scaffold for next-generation STING antagonists
· Advances understanding of STING structural regulation
Further development may yield more selective and clinically optimized STING inhibitors.
Read More:
Background
The cGAS–STING pathway detects cytosolic double-stranded DNA. Upon DNA sensing:
1. Cyclic GMP-AMP synthase (cGAS) produces 2’3’ cyclic GMP-AMP (cGAMP)
2. cGAMP binds STING
3. STING undergoes conformational change and oligomerization
4. Tank-bindining kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) activation occurs
5. Type I interferon and nuclear factor-κB (NF-κB)–dependent cytokines are produced
Aberrant STING activation is implicated in:
· SAVI
· AGS
· Coatomer subunit a (COPA) syndrome
· Systemic lupus erythematosus (SLE)
· Neurodegenerative diseases
Oligomerization of STING, involving Cys148 (human) / Cys147 (mouse), is required for signalling.
Prior inhibitors (e.g., H-151) targeted palmitoylation. Novel strategies are needed to
directly inhibit STING activation mechanisms.
What the Study Found
Mechanism
· BB-Cl-amidine covalently modifies Cys148 in human STING.
· This modification blocks STING oligomerization.
· Inhibition is independent of protein arginine deaminase (PAD) enzyme inhibition.
Cellular Effects
· Reduced phosphorylation of STING, TBK1, IRF3, NF-κB
· Reduced interferon-b (IFN-β) and interferon-stimulated genes (ISG) transcription
· Blocked STING-dependent autophagy
· No inhibition of other innate immune receptors
In Vivo Findings
Using a three prime repair exonuclease 1 (Trex1)D18N/D18N mouse model of AGS:
· BB-Cl-amidine improved survival
· Reduced splenomegaly
· Reduced myocarditis and cardiac fibrosis
Specificity
· STING identified via chemo proteomics as a direct target.
· Effect persists in PAD2/PAD4 knockout cells.
Citation
Humphries et al., Proc Natl Acad Sci U S A. 2023 Aug 15;120(33):e2305420120
Authors
Humphries F, Shmuel-Galia L, Jiang Z, Zhou JY, Barasa L, Mondal S, Wilson R, Sultana N, Shaffer SA, Ng SL, Pesiridis GS, Thompson PR, Fitzgerald KA.
Date of publication 7/8/2023 · Link 10.1073/pnas.2305420120