Design, Synthesis and Biological Evaluation of (2′,5′ and 3′5′-Linked) cGAMP Analogs that Activate Stimulator of Interferon Genes (STING)
Stimulator of interferon genes (STING) is an endoplasmic reticulum adaptor transmembrane protein that plays a pivotal role in innate immune system. STING agonists, such as endogenous cyclic dinucleotide (CDN) cyclic GMP-AMP (cGAMP), have been used in diverse clinical research for immunogenic tumor c...
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| Format: | Article |
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MDPI AG
2020-11-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/22/5285 |
| _version_ | 1797548043984175104 |
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| author | Xin Xie Junyi Liu Xiaowei Wang |
| author_facet | Xin Xie Junyi Liu Xiaowei Wang |
| author_sort | Xin Xie |
| collection | DOAJ |
| description | Stimulator of interferon genes (STING) is an endoplasmic reticulum adaptor transmembrane protein that plays a pivotal role in innate immune system. STING agonists, such as endogenous cyclic dinucleotide (CDN) cyclic GMP-AMP (cGAMP), have been used in diverse clinical research for immunogenic tumor clearance, antiviral treatments and vaccine adjuvants. CDNs containing noncanonical mixed 3′-5′ and 2′-5′ phosphodiester linkages show higher potency in the activation of the STING pathway. In this study, a series of 2′3′-CDNs were designed and synthesized through a modified one-pot strategy. We then established a surface plasmon resonance (SPR)-based binding assay to quantify the binding affinities of synthesized CDNs for human STING, which requested a minuscule amount of sample without any pretreatment. Using this assay, we identified compound <b>8d</b> (K<sub>D</sub> = 0.038 μM), a novel CDN that showed higher binding affinity with hSTING than cGAMP (K<sub>D</sub> = 0.543 μM). Cellular assays confirmed that <b>8d</b> could trigger the expression of type I IFNs and other proinflammatory cytokines more robust than cGAMP. <b>8d</b> also exhibited more resistant than cGAMP to enzymatic cleavage in vitro, indicating the successful improvement in drug availability. These findings provide guidelines for the design and structural optimization of CDNs as STING agonists. |
| first_indexed | 2024-03-10T14:53:48Z |
| format | Article |
| id | doaj.art-54599637405949fa93af2408c8e7930e |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T14:53:48Z |
| publishDate | 2020-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-54599637405949fa93af2408c8e7930e2023-11-20T20:47:13ZengMDPI AGMolecules1420-30492020-11-012522528510.3390/molecules25225285Design, Synthesis and Biological Evaluation of (2′,5′ and 3′5′-Linked) cGAMP Analogs that Activate Stimulator of Interferon Genes (STING)Xin Xie0Junyi Liu1Xiaowei Wang2Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, ChinaDepartment of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, ChinaDepartment of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, ChinaStimulator of interferon genes (STING) is an endoplasmic reticulum adaptor transmembrane protein that plays a pivotal role in innate immune system. STING agonists, such as endogenous cyclic dinucleotide (CDN) cyclic GMP-AMP (cGAMP), have been used in diverse clinical research for immunogenic tumor clearance, antiviral treatments and vaccine adjuvants. CDNs containing noncanonical mixed 3′-5′ and 2′-5′ phosphodiester linkages show higher potency in the activation of the STING pathway. In this study, a series of 2′3′-CDNs were designed and synthesized through a modified one-pot strategy. We then established a surface plasmon resonance (SPR)-based binding assay to quantify the binding affinities of synthesized CDNs for human STING, which requested a minuscule amount of sample without any pretreatment. Using this assay, we identified compound <b>8d</b> (K<sub>D</sub> = 0.038 μM), a novel CDN that showed higher binding affinity with hSTING than cGAMP (K<sub>D</sub> = 0.543 μM). Cellular assays confirmed that <b>8d</b> could trigger the expression of type I IFNs and other proinflammatory cytokines more robust than cGAMP. <b>8d</b> also exhibited more resistant than cGAMP to enzymatic cleavage in vitro, indicating the successful improvement in drug availability. These findings provide guidelines for the design and structural optimization of CDNs as STING agonists.https://www.mdpi.com/1420-3049/25/22/5285STING agonistcyclic dinucleotides (CDNs)SPRimmunotherapy |
| spellingShingle | Xin Xie Junyi Liu Xiaowei Wang Design, Synthesis and Biological Evaluation of (2′,5′ and 3′5′-Linked) cGAMP Analogs that Activate Stimulator of Interferon Genes (STING) Molecules STING agonist cyclic dinucleotides (CDNs) SPR immunotherapy |
| title | Design, Synthesis and Biological Evaluation of (2′,5′ and 3′5′-Linked) cGAMP Analogs that Activate Stimulator of Interferon Genes (STING) |
| title_full | Design, Synthesis and Biological Evaluation of (2′,5′ and 3′5′-Linked) cGAMP Analogs that Activate Stimulator of Interferon Genes (STING) |
| title_fullStr | Design, Synthesis and Biological Evaluation of (2′,5′ and 3′5′-Linked) cGAMP Analogs that Activate Stimulator of Interferon Genes (STING) |
| title_full_unstemmed | Design, Synthesis and Biological Evaluation of (2′,5′ and 3′5′-Linked) cGAMP Analogs that Activate Stimulator of Interferon Genes (STING) |
| title_short | Design, Synthesis and Biological Evaluation of (2′,5′ and 3′5′-Linked) cGAMP Analogs that Activate Stimulator of Interferon Genes (STING) |
| title_sort | design synthesis and biological evaluation of 2 5 and 3 5 linked cgamp analogs that activate stimulator of interferon genes sting |
| topic | STING agonist cyclic dinucleotides (CDNs) SPR immunotherapy |
| url | https://www.mdpi.com/1420-3049/25/22/5285 |
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