Enzymatic synthesis of 2′-ara and 2′-deoxy analogues of c-di-GMP

Shchokolova, Anastasia S.; Рымко, А. Н.; Квач, С В; Shabunya, Polina; Fatykhava, S. A.; Зинченко, А. И.

doi:10.1080/15257770.2015.1006775

Cited by 5 publications

(4 citation statements)

References 12 publications

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“…CDNs, as a much smaller type of nucleoside-based agonist, take advantage of synthetic chemistry. Despite the developed enzymatic synthesis of natural CDNs, , many studies have strived to improve the stability, adjuvant potency and chemical synthesis of natural CDN and CDN mimetics in recent years. CDN mimetics with different linkages have been reported (Figure a).…”

Section: Adjuvants For Enhancing Vaccinationmentioning

confidence: 99%

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Chemical Strategies to Boost Cancer Vaccines

2020

Chem. Rev.

121

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Personalized cancer vaccines (PCVs) are reinvigorating vaccine strategies in cancer immunotherapy. In contrast to adoptive T-cell therapy and checkpoint blockade, the PCV strategy modulates the innate and adaptive immune systems with broader activation to redeploy antitumor immunity with individualized tumor-specific antigens (neoantigens). Following a sequential scheme of tumor biopsy, mutation analysis, and epitope prediction, the administration of neoantigens with synthetic long peptide (SLP) or mRNA formulations dramatically improves the population and activity of antigen-specific CD4+ and CD8+ T cells. Despite the promising prospect of PCVs, there is still great potential for optimizing prevaccination procedures and vaccine potency. In particular, the arduous development of tumor-associated antigen (TAA)-based vaccines provides valuable experience and rational principles for augmenting vaccine potency which is expected to advance PCV through the design of adjuvants, delivery systems, and immunosuppressive tumor microenvironment (TME) reversion since current personalized vaccination simply admixes antigens with adjuvants. Considering the broader application of TAA-based vaccine design, these two strategies complement each other and can lead to both personalized and universal therapeutic methods. Chemical strategies provide vast opportunities for (1) exploring novel adjuvants, including synthetic molecules and materials with optimizable activity, (2) constructing efficient and precise delivery systems to avoid systemic diffusion, improve biosafety, target secondary lymphoid organs, and enhance antigen presentation, and (3) combining bioengineering methods to innovate improvements in conventional vaccination, "smartly" re-educate the TME, and modulate antitumor immunity. As chemical strategies have proven versatility, reliability, and universality in the design of T cell-and B cell-based antitumor vaccines, the union of such numerous chemical methods in vaccine construction is expected to provide new vigor and vitality in cancer treatment.

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Section: Adjuvants For Enhancing Vaccinationmentioning

confidence: 99%

“…CDNs, as a much smaller type of nucleosidebased agonist, take advantage of synthetic chemistry. Despite the developed enzymatic synthesis of natural CDNs, 253,254 have been reported (Figure 4a). For example, Jones and others synthesized a series of CDG mimetics with thiourea, urea, carbodiimide, and guanidinium linkages.…”

Section: Glycoside-based Agonistsmentioning

confidence: 99%

Chemical Strategies to Boost Cancer Vaccines

2020

Chem. Rev.

121

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“…Among the chemistry reported for the synthesis of c-di-GMP analogs, some features are of important consideration: versatility of the chemistry, ease to scale up the process, and to purify the final product. It is worth noting that c-di-GMP [ 34 , 35 ], c-di-araGMP and c-di-dGMP [ 36 ], and other analogs [ 37 ], 3′3′-cGAMP and 2′3′-cGAMP [ 38 , 39 ] and their analogs [ 39 , 40 ] have also been generated enzymatically.…”

Section: C-di-gmp and Analogs Generated To Datementioning

confidence: 99%

The Promise and Challenges of Cyclic Dinucleotides as Molecular Adjuvants for Vaccine Development

Yan

Chen

2021

Vaccines

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Cyclic dinucleotides (CDNs), originally discovered as bacterial second messengers, play critical roles in bacterial signal transduction, cellular processes, biofilm formation, and virulence. The finding that CDNs can trigger the innate immune response in eukaryotic cells through the stimulator of interferon genes (STING) signalling pathway has prompted the extensive research and development of CDNs as potential immunostimulators and novel molecular adjuvants for induction of systemic and mucosal innate and adaptive immune responses. In this review, we summarize the chemical structure, biosynthesis regulation, and the role of CDNs in enhancing the crosstalk between host innate and adaptive immune responses. We also discuss the strategies to improve the efficient delivery of CDNs and the recent advance and future challenges in the development of CDNs as potential adjuvants in prophylactic vaccines against infectious diseases and in therapeutic vaccines against cancers.

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“…Li 等[19] 基于小鼠 cGAS(残基 147～507)蛋白在鲱鱼睾丸 DNA (htDNA)存在下催化 ATPαS 和 GTP 合成了一种抗水解的 2',3'-cGAMP 的双硫代磷酸酯类似物(2',3'-cG s A s MP, 30). 与 2',3'-cGAMP 相比, 化合物 30 在体外与 hSTING 有类似的亲和力, 在诱导人类 THP-1 单核细胞分泌 IFN-β 方面的效力强十倍, 并利用鼠源细胞证明了双磷硫代修饰可提升 CDN 的抗水解能力, 进而提高其激活免疫反应的效力.2015 年, Zinchenko 等[61] 采用 DGC 酶催化 araGTP或 dGTP, 分别合成了 c-di-araGMP 和 c-di-dGMP. 反应 18 h 后产物收率达到 95%以上, 纯化产率约 80%, 具有用于 CDN 大规模生产的潜力.2019 年, Birkuš 等[62] 利用人、小鼠和鸡的 cGAS 酶制备了 33 个 2',3'-CDN, 并在细胞层面测试了这些 CDN 对不同的 STING 突变体的亲和力.…”

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Progress on the Synthesis and Activity of Cyclic Dinucleotides as Stimulator of Interferon Gene (STING) Agonists

Wang¹,

Li²

2023

Chinese Journal of Organic Chemistry

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Cyclic dinucleotide is the agonist of cyclic guanosine-adenosine synthase-stimulator of interferon genes (cGAS-STING) innate immune signal pathway. At present, four kinds of natural STING cyclic dinucleotide agonists have been discovered. In recent years, with the revelation of the mechanism of cGAS-STING pathway, the activation of STING pathway for immunotherapy has become a hot topic. The modification of cyclic dinucleotides to improve their drug activities and properties has become an important means to promote their application in clinical treatment. Here, the important progress in the synthesis and activity of cyclic dinucleotides as STING agonists in recent years is reviewed. Keywords cyclic guanosine-adenosine synthase-stimulator of interferon genes (cGAS-STING); cyclic dinucleotide; chemical synthesis; biosynthesis; drug activity 干扰素基因刺激蛋白(STING)是调控天然免疫信号通路的重要蛋白, 在免疫细胞中广泛表达. STING 蛋白在结合内源或外源环二核苷酸(CDNs)化合物后, 诱导 I 型干扰素和促炎细胞因子的表达, 从而引起免疫活化 [1] . 随着免疫治疗领域的迅速发展 [2] , 利用环二核苷酸类 STING 激动剂来调控 STING 信号通路已成为免疫治疗的新途径 [3] , 天然环二核苷酸激动剂及其类似物的合成由于其重要应用价值也成为近年来的研究热点 [4] . 本文综述了作为 STING 激动剂的环二核苷酸类化合物的研究进展, 重点介绍了环二核苷酸类化合物的合成方法及药物活性研究的最新进展.

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Enzymatic synthesis of 2′-ara and 2′-deoxy analogues of c-di-GMP

Cited by 5 publications

References 12 publications

Chemical Strategies to Boost Cancer Vaccines

Chemical Strategies to Boost Cancer Vaccines

The Promise and Challenges of Cyclic Dinucleotides as Molecular Adjuvants for Vaccine Development

Progress on the Synthesis and Activity of Cyclic Dinucleotides as Stimulator of Interferon Gene (STING) Agonists

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