Discovery of Novel STING Inhibitors Based on the Structure of the Mouse STING Agonist DMXAA
The stimulator-of-interferon-gene (STING) protein is involved in innate immunity. The drug DMXAA (5,6-dimethylxanthenone-4-acetic acid) proved to be a potent murine-STING (mSTING) agonist but had little effect on human-STING (hSTING). In this paper, we draw upon the comparison of different crystal s...
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| Format: | Article |
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MDPI AG
2023-03-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/7/2906 |
| _version_ | 1797607430394216448 |
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| author | Jiajia Chang Shi Hou Xinlin Yan Wei Li Junhai Xiao |
| author_facet | Jiajia Chang Shi Hou Xinlin Yan Wei Li Junhai Xiao |
| author_sort | Jiajia Chang |
| collection | DOAJ |
| description | The stimulator-of-interferon-gene (STING) protein is involved in innate immunity. The drug DMXAA (5,6-dimethylxanthenone-4-acetic acid) proved to be a potent murine-STING (mSTING) agonist but had little effect on human-STING (hSTING). In this paper, we draw upon the comparison of different crystal structures and protein-ligand interaction relationships analysis to venture the hypothesis that the drug design of DMXAA variants has the potential to convert STING agonists to inhibitors. Based on our previous discovery of two DMXAA analogs, <b>3</b> and <b>4</b> (both could bind to STING), we structurally optimized them and synthesized new derivatives, respectively. In binding assays, we found compounds <b>11</b> and <b>27</b> to represent STING binders that were superior to the original structures and discussed the structure-activity relationships. All target compounds were inactive in cellular assays for the screening of STING agonistic activity. Gratifyingly, we identified <b>11</b> and <b>27</b> as STING inhibitors with micromolar activity in both hSTING and mSTING pathways. In addition, <b>11</b> and <b>27</b> inhibited the induction of interferon and inflammatory cytokines activated by 2′3′-cGAMP without apparent cytotoxicity. These findings break the rigid thinking that DMXAA provides the structural basis specifically for STING agonists and open up more possibilities for developing novel STING agonists or inhibitors. |
| first_indexed | 2024-03-11T05:30:58Z |
| format | Article |
| id | doaj.art-a642f340b6214e62817955b40fcc032b |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-11T05:30:58Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-a642f340b6214e62817955b40fcc032b2023-11-17T17:10:42ZengMDPI AGMolecules1420-30492023-03-01287290610.3390/molecules28072906Discovery of Novel STING Inhibitors Based on the Structure of the Mouse STING Agonist DMXAAJiajia Chang0Shi Hou1Xinlin Yan2Wei Li3Junhai Xiao4National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaNational Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaNational Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaNational Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaNational Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaThe stimulator-of-interferon-gene (STING) protein is involved in innate immunity. The drug DMXAA (5,6-dimethylxanthenone-4-acetic acid) proved to be a potent murine-STING (mSTING) agonist but had little effect on human-STING (hSTING). In this paper, we draw upon the comparison of different crystal structures and protein-ligand interaction relationships analysis to venture the hypothesis that the drug design of DMXAA variants has the potential to convert STING agonists to inhibitors. Based on our previous discovery of two DMXAA analogs, <b>3</b> and <b>4</b> (both could bind to STING), we structurally optimized them and synthesized new derivatives, respectively. In binding assays, we found compounds <b>11</b> and <b>27</b> to represent STING binders that were superior to the original structures and discussed the structure-activity relationships. All target compounds were inactive in cellular assays for the screening of STING agonistic activity. Gratifyingly, we identified <b>11</b> and <b>27</b> as STING inhibitors with micromolar activity in both hSTING and mSTING pathways. In addition, <b>11</b> and <b>27</b> inhibited the induction of interferon and inflammatory cytokines activated by 2′3′-cGAMP without apparent cytotoxicity. These findings break the rigid thinking that DMXAA provides the structural basis specifically for STING agonists and open up more possibilities for developing novel STING agonists or inhibitors.https://www.mdpi.com/1420-3049/28/7/2906STINGDMXAAspecies selectivitySTING agonistSTING inhibitor |
| spellingShingle | Jiajia Chang Shi Hou Xinlin Yan Wei Li Junhai Xiao Discovery of Novel STING Inhibitors Based on the Structure of the Mouse STING Agonist DMXAA Molecules STING DMXAA species selectivity STING agonist STING inhibitor |
| title | Discovery of Novel STING Inhibitors Based on the Structure of the Mouse STING Agonist DMXAA |
| title_full | Discovery of Novel STING Inhibitors Based on the Structure of the Mouse STING Agonist DMXAA |
| title_fullStr | Discovery of Novel STING Inhibitors Based on the Structure of the Mouse STING Agonist DMXAA |
| title_full_unstemmed | Discovery of Novel STING Inhibitors Based on the Structure of the Mouse STING Agonist DMXAA |
| title_short | Discovery of Novel STING Inhibitors Based on the Structure of the Mouse STING Agonist DMXAA |
| title_sort | discovery of novel sting inhibitors based on the structure of the mouse sting agonist dmxaa |
| topic | STING DMXAA species selectivity STING agonist STING inhibitor |
| url | https://www.mdpi.com/1420-3049/28/7/2906 |
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