Cyclic Dinucleotides

Xie Z, et al. Advanced Agrochem, 2024, 3(4), 337-343.

Cyclic dinucleotides (CDNs), a class of signaling molecules with important physiological roles in various organisms, have recently been explored for their potential bioactivity in agricultural pest control. In this study, ten types of CDNs, containing adenine and guanine bases with different internucleotide linkages (3′,3′; 2′,3′; 2′,2′), were synthesized and tested for their antifeedant and insecticidal activities against common Lepidoptera pests, including Spodoptera frugiperda, Mythimna separata, and Helicoverpa armigera.
Bioassay results revealed that 3′,3′-c-di-AMP exhibited the highest antifeedant activity, with an EC50 of 0.59 mg/L against M. separata larvae, while 2′,3′-c-di-AMP showed significant insecticidal activity with an LC50 of 55.4 mg/L against the same larvae. Transcriptomic analysis further demonstrated that these CDNs impacted the growth and development of insects, with 3′,3′-c-di-AMP inducing immune inflammation, suggesting a mechanism involving insect immune system stimulation. These findings indicate that cyclic dinucleotides can interfere with the normal physiological processes of insects, opening new avenues for the management of agricultural pests. The antifeedant and insecticidal properties of CDNs, particularly 3′,3′-c-di-AMP and 2′,3′-c-di-AMP, provide valuable insights into their potential use in pest control strategies.

Imana ZN, et al. Biomedicine & Pharmacotherapy, 2024, 181, 117692.

Cyclic dinucleotides (c-di-AMP), as agonists of the stimulator of interferon genes (STING), have shown promising potential in cancer immunotherapy, particularly in combination with other immune modulators. In a recent study, c-di-AMP was used in conjunction with CpG-oligodeoxynucleotide (CpG-ODN) to enhance anti-tumor immunity in head and neck cancer. The combination of these two agonists was shown to significantly inhibit tumor growth, demonstrating a cooperative effect that is more potent than either treatment alone.
The mechanism underlying this enhanced tumor suppression involves the modulation of immune responses. CpG-ODN (a Toll-like receptor 9 agonist) primarily induces a Th1-dominant immune response, characterized by increased production of pro-inflammatory cytokines. In contrast, c-di-AMP initially promotes a Th2-biased cytokine profile. However, when combined, these two agents synergistically enhance Th1 cytokine production while reducing Th2 cytokines, leading to the polarization of M1 macrophages and the accumulation of dendritic cells and T cells in the tumor microenvironment. This reprogramming of the immune response fosters a more favorable environment for T cell-mediated tumor killing.
The anti-tumor effect of c-di-AMP, when used in combination with CpG-ODN, is macrophage-dependent but does not directly induce M1 macrophage polarization. Instead, it relies on a reprogrammed cytokine profile that shapes the immune landscape in favor of tumor suppression. Furthermore, the combination shows cooperative activity with anti-PD-1 therapy, enhancing the efficacy of immune checkpoint inhibition.

Cai H, et al. Immunity, 2023, 56(9), 1991-2005.e9

Cyclic dinucleotides (CDNs), including 2′3′-cGAMP, are key signaling molecules involved in innate immunity, particularly through the activation of the STING pathway. While CDNs such as 2′3′-cGAMP are well-known in mammals for their role in sensing cytosolic DNA, their function in Drosophila species, particularly in antiviral defense, remains an area of active exploration. Recent research has expanded our understanding of CDN-mediated immunity in Drosophila, shedding light on the evolutionary dynamics of cGAS-like receptors (cGLRs) and their roles in pathogen detection.
In this study, researchers explored the role of CDNs in 14 Drosophila species across 50 million years of evolution. They found that while 2′3′-cGAMP and 3′2′-cGAMP failed to control infection by Drosophila C virus in certain species such as D. serrata, the production of other CDNs, notably 2′3′-c-di-GMP, was more effective in activating the STING pathway. Notably, 2′3′-c-di-GMP was identified as a more potent STING agonist than cGAMP in D. melanogaster, and it also elicited a robust antiviral transcriptional response in D. serrata, demonstrating its superior ability to trigger antiviral immunity.

Aikins M. E, et al. Journal of Controlled Release, 2024, 368, 768-779.

Acute myeloid leukemia (AML) is a challenging cancer with a low survival rate due to tumor relapse and inadequate immune activation. A promising strategy for combating AML involves the use of cyclic dinucleotides (CDNs), particularly c-di-AMP, which act as potent STING agonists.
In this study, the researchers developed a lipid-based nanoparticle platform (CMP) loaded with Mn²⁺ and c-di-AMP (CDA) to activate the STING pathway. Systemic administration of this CMP nanoparticle formulation in a mouse model of disseminated AML led to significant anti-tumor efficacy. The treatment activated both innate and adaptive immune responses, improving cytotoxic T-cell activity against AML cells. Importantly, when combined with immune checkpoint blockade targeting cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4), the therapy enhanced immune activation and extended survival in the treated mice, even after re-challenging with AML cells. This research demonstrates that STING activation using c-di-AMP nanoparticles can not only enhance immune surveillance and response against AML but also promote long-term immunity through immune memory formation.

Onyedibe KI, et al. Journal of Proteomics, 2023, 279, 104869.

Cyclic dinucleotides (CDNs), particularly 2'3'-cGAMP, play a crucial role in innate immunity by activating Stimulator of Interferon Genes (STING), which in turn triggers the production of cytokines and interferons, primarily via the TBK1 pathway. However, the broader effects of 2'3'-cGAMP on cellular signaling pathways have not been fully explored. This study employed unbiased proteomics and phosphoproteomics to investigate the extensive impact of 2'3'-cGAMP on the phosphoproteome in Jurkat T-cells. The results revealed that beyond the canonical STING-TBK1-IRF3 signaling axis, 2'3'-cGAMP modulates multiple kinase activities, influencing DNA repair, apoptosis, and cell cycle regulation.
The treatment with 2'3'-cGAMP led to upregulation of key antiviral immune response proteins, such as Arginase 2 (Arg2) and RIG-I, alongside proteins involved in ISGylation, including HERC5 and ISG15. Additionally, downregulation of UBE2C, a ubiquitin-conjugating enzyme, was observed. Notably, kinases implicated in DNA damage repair and cell cycle control were differentially phosphorylated, underscoring the complexity of 2'3'-cGAMP's impact on cellular processes.
These findings highlight 2'3'-cGAMP's broader effects on the cellular proteome, demonstrating its potential to influence multiple signaling pathways beyond the classical TBK1/IKK-NF-κB axis.