Targeting STING oligomerization with small-molecule inhibitors

  • Proc Natl Acad Sci U S A. 2023 Aug 15;120(33):e2305420120. doi: 10.1073/pnas.2305420120.
Fiachra Humphries  #  1 ,  Liraz Shmuel-Galia  #  1 ,  Zhaozhao Jiang  1 ,  Jeffrey Y Zhou  1 ,  Leonard Barasa  2 ,  Santanu Mondal  2  3 ,  Ruth Wilson  1 ,  Nadia Sultana  2  4 ,  Scott A Shaffer  2  4 ,  Sze-Ling Ng  5 ,  G Scott Pesiridis  5 ,  Paul R Thompson  2 ,  Katherine A Fitzgerald  1
Affiliations
  • 1. Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605.
  • 2. Program in Chemical Biology, Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA 01605.
  • 3. Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, New Delhi 110016, India.
  • 4. Mass Spectrometry Facility, Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA 01545.
  • 5. Immunology Research Unit, GlaxoSmithKline, Philadelphia, PA 19426.
  • # Contributed equally.
PMID: 37549268 DOI: 10.1073/pnas.2305420120
Abstract

Stimulator of interferon genes (STING) is an essential adaptor protein required for the inflammatory response to cytosolic DNA. dsDNA activates cGAS to generate cGAMP, which binds and activates STING triggering a conformational change, oligomerization, and the IRF3- and NFκB-dependent transcription of type I Interferons (IFNs) and inflammatory cytokines, as well as the activation of Autophagy. Aberrant activation of STING is now linked to a growing number of both rare as well as common chronic inflammatory diseases. Here, we identify and characterize a potent small-molecule inhibitor of STING. This compound, BB-Cl-amidine inhibits STING signaling and production of type I IFNs, IFN-stimulated genes (ISGs) and NFκB-dependent cytokines, but not other Pattern Recognition Receptors. In vivo, BB-Cl-amidine alleviated pathology resulting from accrual of cytosolic DNA in Trex-1 mutant mice. Mechanistically BB-Cl-amidine inhibited STING oligomerization through modification of Cys148. Collectively, our work uncovers an approach to inhibit STING activation and highlights the potential of this strategy for the treatment of STING-driven inflammatory diseases.

Keywords
Trex-1; cytokines; protein arginine deiminases; small-molecule inhibitor; stimulator of interferon genes.
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