Control of STING Agonistic/Antagonistic Activity Using Amine-Skeleton-Based c-di-GMP Analogues
Stimulator of Interferon Genes (STING) is a type of endoplasmic reticulum (ER)-membrane receptor. STING is activated by a ligand binding, which leads to an enhancement of the immune-system response. Therefore, a STING ligand can be used to regulate the immune system in therapeutic strategies. Howeve...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-06-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/12/6847 |
| _version_ | 1797486312857534464 |
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| author | Yuta Yanase Genichiro Tsuji Miki Nakamura Norihito Shibata Yosuke Demizu |
| author_facet | Yuta Yanase Genichiro Tsuji Miki Nakamura Norihito Shibata Yosuke Demizu |
| author_sort | Yuta Yanase |
| collection | DOAJ |
| description | Stimulator of Interferon Genes (STING) is a type of endoplasmic reticulum (ER)-membrane receptor. STING is activated by a ligand binding, which leads to an enhancement of the immune-system response. Therefore, a STING ligand can be used to regulate the immune system in therapeutic strategies. However, the natural (or native) STING ligand, cyclic-di-nucleotide (CDN), is unsuitable for pharmaceutical use because of its susceptibility to degradation by enzymes and its low cell-membrane permeability. In this study, we designed and synthesized CDN derivatives by replacing the sugar-phosphodiester moiety, which is responsible for various problems of natural CDNs, with an amine skeleton. As a result, we identified novel STING ligands that activate or inhibit STING. The cyclic ligand <b>7</b>, with a cyclic amine structure containing two guanines, was found to have agonistic activity, whereas the linear ligand <b>12</b> showed antagonistic activity. In addition, these synthetic ligands were more chemically stable than the natural ligands. |
| first_indexed | 2024-03-09T23:32:23Z |
| format | Article |
| id | doaj.art-abba75019b0947798afa2063d7ce93a0 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T23:32:23Z |
| publishDate | 2022-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-abba75019b0947798afa2063d7ce93a02023-11-23T17:07:49ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-06-012312684710.3390/ijms23126847Control of STING Agonistic/Antagonistic Activity Using Amine-Skeleton-Based c-di-GMP AnaloguesYuta Yanase0Genichiro Tsuji1Miki Nakamura2Norihito Shibata3Yosuke Demizu4National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki 210-9501, JapanNational Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki 210-9501, JapanNational Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki 210-9501, JapanNational Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki 210-9501, JapanNational Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki 210-9501, JapanStimulator of Interferon Genes (STING) is a type of endoplasmic reticulum (ER)-membrane receptor. STING is activated by a ligand binding, which leads to an enhancement of the immune-system response. Therefore, a STING ligand can be used to regulate the immune system in therapeutic strategies. However, the natural (or native) STING ligand, cyclic-di-nucleotide (CDN), is unsuitable for pharmaceutical use because of its susceptibility to degradation by enzymes and its low cell-membrane permeability. In this study, we designed and synthesized CDN derivatives by replacing the sugar-phosphodiester moiety, which is responsible for various problems of natural CDNs, with an amine skeleton. As a result, we identified novel STING ligands that activate or inhibit STING. The cyclic ligand <b>7</b>, with a cyclic amine structure containing two guanines, was found to have agonistic activity, whereas the linear ligand <b>12</b> showed antagonistic activity. In addition, these synthetic ligands were more chemically stable than the natural ligands.https://www.mdpi.com/1422-0067/23/12/6847STINGcyclic dinucleotideaminesdrug designagonistantagonist |
| spellingShingle | Yuta Yanase Genichiro Tsuji Miki Nakamura Norihito Shibata Yosuke Demizu Control of STING Agonistic/Antagonistic Activity Using Amine-Skeleton-Based c-di-GMP Analogues International Journal of Molecular Sciences STING cyclic dinucleotide amines drug design agonist antagonist |
| title | Control of STING Agonistic/Antagonistic Activity Using Amine-Skeleton-Based c-di-GMP Analogues |
| title_full | Control of STING Agonistic/Antagonistic Activity Using Amine-Skeleton-Based c-di-GMP Analogues |
| title_fullStr | Control of STING Agonistic/Antagonistic Activity Using Amine-Skeleton-Based c-di-GMP Analogues |
| title_full_unstemmed | Control of STING Agonistic/Antagonistic Activity Using Amine-Skeleton-Based c-di-GMP Analogues |
| title_short | Control of STING Agonistic/Antagonistic Activity Using Amine-Skeleton-Based c-di-GMP Analogues |
| title_sort | control of sting agonistic antagonistic activity using amine skeleton based c di gmp analogues |
| topic | STING cyclic dinucleotide amines drug design agonist antagonist |
| url | https://www.mdpi.com/1422-0067/23/12/6847 |
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