Dual Covalent Targeting of STING Cysteines 292/309 Disrupts Functional Oligomerization and Enables Potent Antagonist
Yuxuan Zhao1,2, Ling Huang1, Wenjing Qin1
1State Key Laboratory of Bioactive Molecules and Druggability Assessment, Department of Radiology, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, China.
Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|March 24, 2026
Summary
Researchers developed a novel STING antagonist by targeting specific cysteine residues. This dual covalent strategy effectively inhibits STING signaling and inflammation, offering a new therapeutic approach for autoimmune diseases.
Area of Science:
- Immunology
- Drug Discovery
- Structural Biology
Background:
- Dysregulated STING (stimulator of interferon genes) activation drives inflammation in autoimmune and autoinflammatory diseases.
- Current STING antagonists often rely on phenotypic screening.
- Targeted inhibition of STING signaling is therapeutically needed.
Purpose of the Study:
- To introduce a rational design strategy for STING antagonists.
- To develop covalent inhibitors targeting the STING C-terminal domain (CTD).
- To identify novel therapeutic agents for STING-driven inflammation.
Main Methods:
- Rational drug design targeting cysteine residues in the STING CTD.
- Covalent warhead repurposing to identify inhibitors.
- Mechanistic studies using site-directed mutagenesis (C292A/C309A).
- In vitro and in vivo evaluation of STING signaling inhibition and therapeutic efficacy.
- Structure-guided optimization of lead compounds.
Main Results:
- Identified P005091, a USP7 inhibitor, as a STING antagonist via dual covalent CTD targeting.
- Demonstrated inhibition is dependent on concurrent engagement of Cys292 and Cys309.
- P005091 potently suppressed STING signaling and type I interferon responses.
- Optimized compounds NTP14 and NTP16 showed enhanced potency and efficacy in preclinical models, including DSS-induced colitis.
Conclusions:
- Dual covalent CTD targeting is a transformative strategy for STING antagonist development.
- This approach effectively inhibits STING signaling and ameliorates STING-driven pathology.
- Opens new therapeutic avenues for treating inflammatory diseases by quenching STING activation at its source.
