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2′,3′‐Cyclic GMP‐AMP (cGAMP) is a cyclic dinucleotide second messenger in which guanosine and adenosine are connected by one 3′‐5′ and one 2′‐5′ phosphodiester linkage. It is formed in the cytosol upon detection of pathogenic DNA by the enzyme guanosine‐monophosphate‐adenosine monophosphate synthase (cGAS). cGAMP subsequently binds to the adaptor protein stimulator of interferon genes (STING) to elicit an innate immune response leading to the production of type I interferons and cytokines. STING agonists are a highly promising avenue for an immuno‐oncological anticancer therapy. A particular challenge with cyclic dinucleotide STING agonists are the two negative charges of the phosphodiester linkages, which strongly reduce the ability of such compounds to penetrate cell membranes. The development of cell‐permeable STING agonists that can stimulate the immune system enhancing their anticancer potency is currently of utmost importance in the field. Herein, we report the development of a dideoxy derivative of cGAMP as a phosphotriester prodrug, where the negative charge of the phosphate backbone has been masked with a thioester. We found that this thioester‐protected compound features a dramatic increase in its cellular potency that rises from EC50=5 μM to 25 nM. The new compound is envisioned to enable an efficient STING‐agonist‐based anticancer therapy. [ABSTRACT FROM AUTHOR]

2′3′‐zyklisches GMP‐AMP (cGAMP) ist ein zyklischer Dinukleotid‐Botenstoff, bei dem Guanosin und Adenosin durch eine 3′‐5′‐ und eine 2′‐5′‐Phosphodiester‐Bindung verbunden sind. Es wird im Zytosol bei der Erkennung pathogener DNA durch das Enzym Guanosin‐Monophosphat‐Adenosin‐Monophosphat‐Synthase (cGAS) gebildet. cGAMP bindet anschließend an das Adapterprotein Stimulator der Interferon‐Gene (STING), um eine angeborene Immunantwort auszulösen, die zur Produktion von Typ‐I‐Interferonen und Zytokinen führt. STING‐Agonisten sind ein vielversprechender Ansatzpunkt für eine immunonkologische Krebstherapie. Eine besondere Herausforderung bei zyklischen Dinukleotid‐STING‐Agonisten sind die beiden negativen Ladungen der Phosphodiester‐Bindungen, die die Fähigkeit, Zellmembranen zu durchdringen, stark einschränken. Die Entwicklung zellpermeabler STING‐Agonisten, die das Immunsystem stimulieren können und damit ihre krebsbekämpfende Wirkung verstärken, ist derzeit von größter Bedeutung. Hier berichten wir über die Entwicklung eines Dideoxy‐Derivats von cGAMP als Phosphotriester‐Prodrug, bei dem die negative Ladung des Phosphatrückgrats durch einen Thioester maskiert wurde. Wir konnten feststellen, dass diese Thioester‐geschützte Verbindung eine drastische Steigerung ihrer zellulären Wirksamkeit aufweist, die von EC50=5 μM auf 25 nM ansteigt. Die neue Verbindung soll eine effiziente Krebstherapie auf der Basis von STING‐Agonisten ermöglichen. [ABSTRACT FROM AUTHOR]

Nucleic acids in the form of siRNA, antisense oligonucleotides or mRNA are currently explored as new promising modalities in the pharmaceutical industry. Particularly, the success of mRNA‐vaccines against SARS‐CoV‐2, along with the successful development of the first sugar‐modified siRNA therapeutics has inspired the field. The development of nucleic acid therapeutics requires efficient chemistry to link oligonucleotides to chemical structures that can improve stability, boost cellular uptake, or enable specific targeting. For the siRNA therapeutics currently in use, modification of the 3′‐end of the oligonucleotides with triple‐N‐acetylgalactosamine (GalNAc)3 was shown to be of significance. This modification is currently achieved through cumbersome multistep synthesis and subsequent loading onto the solid support material. Herein, we report the development of a bifunctional click‐reactive linker that allows the modification of oligonucleotides in a tandem click reaction with multiple sugars, regardless of the position within the oligonucleotide, with remarkable efficiency and in a one‐pot reaction. [ABSTRACT FROM AUTHOR]

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