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

• Published in: ChemMedChem Vol. 17; no. 2; pp. e202100671 - n/a
• Main Authors: Shang, Mengdi, Lu, Kuan, Guan, Wenli, Cao, Shujie, Ren, Mengtian, Zhou, Chuanzheng
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 19.01.2022
• Subjects: Autoimmune diseases; Autophagy; cGAS-STING pathway; Cyclic dinucleotides; Cyclic GMP; Humans; Immune system; Immunology; Immunomodulation; Immunotherapy; Innate immunity; Interferon regulatory factor 3; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - immunology; Metabolism; Models, Molecular; Molecular Conformation; Neoplasms - immunology; Neoplasms - therapy; Nucleotides; Nucleotides - chemical synthesis; Nucleotides - chemistry; Nucleotides - pharmacology; Nucleotides, Cyclic - chemical synthesis; Nucleotides, Cyclic - chemistry; Nucleotides, Cyclic - pharmacology; Nucleotidyltransferases - antagonists & inhibitors; Nucleotidyltransferases - immunology; Second messengers; Signal transduction; Signal Transduction - drug effects; Signal Transduction - immunology; Signaling; Synthesis; Immunology; Nucleotides; cGAS-STING pathway; Immunotherapy; Cyclic dinucleotides
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.202100671

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‐κB 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. Putting the STING on disease: This review focuses on the discovery, metabolism, and function of 2′,3′‐cGAMP in the cGAS‐STING innate immune signalling axis and summarizes the key advancements in the enzymatic and chemical synthesis of 2′,3′‐cGAMP analogues as STING‐targeting therapeutics.