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Design, Synthesis and Biological Evaluation of (2',5' and 3'5'-Linked) cGAMP Analogs that Activate Stimulator of Interferon Genes (STING).

ABSTRACT: 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 8d (K_D = 0.038 ?M), a novel CDN that showed higher binding affinity with hSTING than cGAMP (K_D = 0.543 ?M). Cellular assays confirmed that 8d could trigger the expression of type I IFNs and other proinflammatory cytokines more robust than cGAMP. 8d 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.

SUBMITTER: Xie X

PROVIDER: S-EPMC7697705 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Design, Synthesis and Biological Evaluation of (2',5' and 3'5'-Linked) cGAMP Analogs that Activate Stimulator of Interferon Genes (STING).

Xie Xin X Liu Junyi J Wang Xiaowei X

Molecules (Basel, Switzerland) 20201112 22

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 stu ...[more]

PMID: 33198423

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Project description:Sjögren syndrome (SS), a chronic autoimmune disorder causing dry mouth, adversely affects the overall oral health in patients. Activation of innate immune responses and excessive production of type I interferons (IFNs) play a critical role in the pathogenesis of this disorder. Recognition of nucleic acids by cytosolic nucleic acid sensors is a major trigger for the induction of type I IFNs. Upon activation, cytosolic DNA sensors can interact with the stimulator of interferon genes (STING) protein, and activation of STING causes increased expression of type I IFNs. The role of STING activation in SS is not known. In this study, to investigate whether the cytosolic DNA sensing pathway influences SS development, female C57BL/6 mice were injected with a STING agonist, dimethylxanthenone-4-acetic acid (DMXAA). Salivary glands (SGs) were studied for gene expression and inflammatory cell infiltration. SG function was evaluated by measuring pilocarpine-induced salivation. Sera were analyzed for cytokines and autoantibodies. Primary SG cells were used to study the expression and activation of STING. Our data show that systemic DMXAA treatment rapidly induced the expression of Ifnb1, Il6, and Tnfa in the SGs, and these cytokines were also elevated in circulation. In contrast, increased Ifng gene expression was dominantly detected in the SGs. The type I innate lymphoid cells present within the SGs were the major source of IFN-?, and their numbers increased significantly within 3 d of treatment. STING expression in SGs was mainly observed in ductal and interstitial cells. In primary SG cells, DMXAA activated STING and induced IFN-? production. The DMXAA-treated mice developed autoantibodies, sialoadenitis, and glandular hypofunction. Our study demonstrates that activation of the STING pathway holds the potential to initiate SS. Thus, apart from viral infections, conditions that cause cellular perturbations and accumulation of host DNA within the cytosol should also be considered as possible triggers for SS.

Dataset Information

Design, Synthesis and Biological Evaluation of (2',5' and 3'5'-Linked) cGAMP Analogs that Activate Stimulator of Interferon Genes (STING).

Publications

Design, Synthesis and Biological Evaluation of (2',5' and 3'5'-Linked) cGAMP Analogs that Activate Stimulator of Interferon Genes (STING).

Similar Datasets

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