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Review
. 2019 Nov 15;182:111591.
doi: 10.1016/j.ejmech.2019.111591. Epub 2019 Aug 8.

STING Modulators: Predictive Significance in Drug Discovery

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Free PMC article
Review

STING Modulators: Predictive Significance in Drug Discovery

Xiangling Cui et al. Eur J Med Chem. .
Free PMC article

Abstract

Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) - stimulator of interferon genes (STING) signaling pathway plays the critical role in the immune response to DNA. Pharmacological modulation of the STING pathway has been well characterized both from structural and functional perspectives, which paves the way for the drug design of small modulators by medicinal chemists. Here, we outline recent progress in studies on the STING pathway, the structure and biological function of STING, the STING related disease, as well as the rationale and progress in the development of STING modulators. Our review demonstrates that STING is a promising drug target, and providing clues for the discovery of novel STING agonists and antagonists for the potential treatment of various disease including microbial infectious diseases, cancer, and autoimmune disease.

Keywords: Immunotherapy; Innate immune response; STING; Small modulators.

Figures

Image 1
Fig. 1
Fig. 1
The cGAS-STING pathway of cytosolic DNA sensing. Cytosolic DNA binds to and activates cGAS, which catalyzes the synthesis of 2′3ʹ-cGAMP from ATP and GTP. 2′3ʹ-cGAMP binds to the ER adaptor STING, which traffics to the ER-Golgi intermediate compartment (ERGIC) and the Golgi apparatus. After the tansmembrane domain of STING is palmitoylated, then palmitoylated STING is clustered to produce oligmerization to recruit TBK1. TBK1 phosphorylates STING, which in turn recruits IRF3 for phosphorylation by TBK1. Phosphorylated IRF3 dimerizes and then enters the nucleus, where it functions with NF-kB to turn on the expression of type I interferons and other immunomodulatory molecules. Furthermore, the ERGIC, which contains cGAMP-bound STING, serves as a membrane source for LC3 recruitment and lipidation through a WIPI2-dependent mechanism. LC3-positive membranes target DNA and pathogens to autophagosomes, which are subsequently fused with lysosomes in a process that requires RAB7 GTPase.
Fig. 2
Fig. 2
A) The schematic of human STING domain organization; B) The left is the full-length of apo human STING in open conformation (PDB code: 6NT5) and the right is chicken STING with cGAMP in a closed conformation (PDB code: 6NT7). The Cys 88 and Cys 91 in transmembrane domain is palmitoylated which may further promote STING oligomerization and subsequent activation of TBK1, colored green and yellow respectively. The appearance of lid region is the feature of closed conformation; C) The globular C-terminal domain of human STING with a large binding pocket (PDB code: 4F9G); D) The densities for the two protomers of the TBK1 dimer are colored gray or blue. The densities for the two STING C-terminal tails are colored yellow (PDB code: 6NT9); E) Phosphorylated STING C-terminal tail in complex with IRF3, colored blue and yellow, respectively. The residue S366(magenta) in STING C-terminal tail is required for STING to be licensed for the interaction with IRF3 (PDB code:5JEJ). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
Fig. 3
Fig. 3
The summary of STING agonists.
Fig. 4
Fig. 4
A) Crystal structure of rat STING in complex with 2′3′-cGAMP (PDB code: 5GRM); B) Crystal structure of hSTING(G230I) in complex with DMXAA (PDB code: 4QXP). The DMXAA, S162, G230 and Q266 are colored green, cyan, red and yellow respectively; C) Crystal structure of human STING in complex with diABZI1 (PDB code: 6DXL); D) Crystal structure of human STING (G230A, H232R, R293Q) in complex with C18 (PDB code: 6MXE). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
Fig. 5
Fig. 5
The structures of STING antagonists.

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