A Click‐Chemistry Linked 2′3′‐cGAMP Analogue

Dialer, Clemens; Stazzoni, Samuele; Drexler, David; Müller, Felix; Veth, Simon; Pichler, Alexander; Okamura, Hirokazu; Witte, Gregor; Hopfner, Karl‐Peter; Carell, Thomas

doi:10.1002/chem.201805409

Cited by 17 publications

(12 citation statements)

References 46 publications

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“…To which extent the synthesis can be transferred to a larger scale cannot be estimated from the data published to date. Another recently published synthesis route based on click chemistry reactions resulted in a 2′3′‐cGAMP analog with neutral linkages that is characterized by a better cell membrane penetrability (Dialer et al, 2019). The labile and charged phosphate groups were replaced by an amide bond and a triazole linkage.…”

Section: Current Chemical and Biocatalytic Synthesis Routesmentioning

confidence: 99%

“…The 20‐step synthesis of this uncharged product resulted in a yield of 1%. Unfortunately, the product lacked affinity towards the STING receptor (Dialer et al, 2019). Beside the solution‐phase synthesis, solid‐phase synthesis of c‐di‐GMP starting from 3′‐phosphate controlled pore glass as carrier material was demonstrated (Kiburu et al, 2008).…”

Section: Current Chemical and Biocatalytic Synthesis Routesmentioning

confidence: 99%

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Biotechnological production of cyclic dinucleotides—Challenges and opportunities

Bartsch

Becker

Rolf

et al. 2022

Biotech & Bioengineering

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Cyclic dinucleotides (CDNs) are widely used secondary signaling molecules in prokaryotic and eukaryotic cells. As strong agonists of the stimulator of interferon genes, they are of great interest for pharmaceutical applications. In particular, cyclic-GMP-AMP and related synthetic CDNs are promising candidates in preclinical work and even some in clinical phase 1 and 2 studies. The comparison of chemical and biocatalytic synthesis routes elucidated that biological CDN synthesis offers some advantages, such as shorter synthesis time, avoiding complex protective group chemistry, and the access to a new spectrum of CDNs. However, the synthesis of CDNs in preparative quantities is still a challenge, since the chemical synthesis of CDNs suffers from low yields and complex synthetic routes and the enzymatically catalyzed synthesis is limited by low product titers and process stability. We aim to review the latest discoveries and recent trends in chemical and biocatalytic synthesis of CDNs with a focus on the synthesis of a huge variety of CDN derivatives. We furthermore consider the most promising biotechnological processes for CDN production by evaluating key figures of the currently known processes.

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Section: Current Chemical and Biocatalytic Synthesis Routesmentioning

confidence: 99%

Section: Current Chemical and Biocatalytic Synthesis Routesmentioning

confidence: 99%

Biotechnological production of cyclic dinucleotides—Challenges and opportunities

Bartsch

Becker

Rolf

et al. 2022

Biotech & Bioengineering

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“…The synthesis of cyclic dinucleotides with nonphosphate linkages is also beyond the scope of enzymatic synthesis. [127] Chemical synthesis provides an alternative approach for the preparation of 2',3'-cGAMP analogues and has complementary advantages with enzymatic synthesis. Chemical synthesis of cyclic dinucleotides can be traced back to the 1950s when Khorana tried to synthesize oligonucleotides based on the phosphodiester method.…”

Section: Chemical Synthesismentioning

confidence: 99%

“…[153][154][155] Recently, Carell reported the synthesis of 2',3'-cGAMP analogues with one amide and one trizole linkage (Scheme 10B). [127] The trizole linkage between the C3' of adenosine and C5' of guanosine is first constructed based on Cu(I)-catalysed click chemistry. Then, the obtained dinucleotide is subjected to cyclization based on the coupling of the 5'-NH 2 of adenosine with the 2'-acetic acid of guanosine.…”

Section: Synthesis Of Neutral 2'3'-cgamp Analoguesmentioning

confidence: 99%

2′,3′‐Cyclic GMP‐AMP Dinucleotides for STING‐Mediated Immune Modulation: Principles, Immunotherapeutic Potential, and Synthesis

Shang

Guan

et al. 2021

ChemMedChem

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The cGAS-STING pathway discovered ten years ago is an important component of the innate immune system. Activation of cGAS-STING triggers downstream signalling, such as TBK1-IRF3, NF-kB and autophagy, which in turn leads to antipathogen responses, durable antitumour immunity or autoimmune diseases. 2',3'-Cyclic GMP-AMP dinucleotides (2',3'-cGAMP), the key second messengers produced by cGAS, play a pivotal role in cGAS-STING signalling by binding and activating STING. Thus, 2',3'-cGAMP has immunotherapeutic potential, which in turn has stimulated research on the design and synthesis of 2',3'-cGAMP analogues for clinical applications over the past ten years. This review presents the discovery, metabolism, and function of 2',3'-cGAMP in the cGAS-STING innate immune signalling axis. The enzymatic and chemical syntheses of 2',3'-cGAMP analogues as STING-targeting therapeutics are also summarized.

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“…Most of the currently reported CDN derivatives are limited to those with a phosphodiester skeleton, which are prone to degradation by PDE [ 48 , 49 , 50 , 51 , 52 , 53 ]. Although several research groups have reported CDN derivatives where the phosphodiester-sugar backbone is replaced with a different linker structure [ 54 , 55 , 56 ], there are no examples of CDN-based STING ligands with substitution of the entire sugar-phosphodiester backbone. In this study, we designed new CDN mimetics with the phosphodiester skeleton replaced by an amine skeleton, which is easy to synthesize and derivatize.…”

Section: Introductionmentioning

confidence: 99%

Control of STING Agonistic/Antagonistic Activity Using Amine-Skeleton-Based c-di-GMP Analogues

Yanase

Tsuji

Nakamura

et al. 2022

IJMS

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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 7, with a cyclic amine structure containing two guanines, was found to have agonistic activity, whereas the linear ligand 12 showed antagonistic activity. In addition, these synthetic ligands were more chemically stable than the natural ligands.

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A Click‐Chemistry Linked 2′3′‐cGAMP Analogue

Cited by 17 publications

References 46 publications

Biotechnological production of cyclic dinucleotides—Challenges and opportunities

Biotechnological production of cyclic dinucleotides—Challenges and opportunities

2′,3′‐Cyclic GMP‐AMP Dinucleotides for STING‐Mediated Immune Modulation: Principles, Immunotherapeutic Potential, and Synthesis

Control of STING Agonistic/Antagonistic Activity Using Amine-Skeleton-Based c-di-GMP Analogues

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