Search

In mammals, the enzyme cGAS senses the presence of cytosolic DNA and synthesizes the cyclic dinucleotide (CDN) 2′3′-cGAMP, which triggers STING-dependent immunity. In Drosophila melanogaster , two cGAS-like receptors (cGLRs) produce 3′2′-cGAMP and 2′3′-cGAMP to activate STING. We explored CDN-mediated immunity in 14 Drosophila species covering 50 million years of evolution and found that 2′3′-cGAMP and 3′2′-cGAMP failed to control infection by Drosophila C virus in D. serrata and two other species. We discovered diverse CDNs produced in a cGLR-dependent manner in response to viral infection in D. melanogaster , including 2′3′-c-di-GMP. This CDN was a more potent STING agonist than cGAMP in D. melanogaster and it also activated a strong antiviral transcriptional response in D. serrata. Our results shed light on the evolution of cGLRs in flies and provide a basis for understanding the function and regulation of this emerging family of pattern recognition receptors in animal innate immunity. [Display omitted] • cGLRs evolve rapidly in Drosophila flies • Viral infection triggers cGLR-dependent production of CDNs in vivo • cGLRs synthesize distinct CDNs, including the previously unrecognized 2′3′-c-di-GMP • 2′3′-c-di-GMP is a more potent STING agonist than cGAMP in several Drosophila species In the model organism Drosophila melanogaster , two cGAS-like receptors participate in antiviral host-defense. Cai et al. explore STING-dependent immunity in several Drosophila species and report that flies encode up to seven cGAS-like receptors, which can produce distinct cyclic dinucleotide signals in response to viral infection. [ABSTRACT FROM AUTHOR]

The activation of stimulator of interferon genes (STING) signaling pathways plays an important role in the innate immune response. Although several STING agonists have been developed recently, the majority of clinical CDN STING agonists are administered by intratumoral (IT) injection. Therefore, there remains a need to develop diverse non-CDN small-molecule STING agonists with systemic administration. Herein, by using a scaffold hopping strategy, we designed a series of thieno [2,3-d]imidazole derivatives as novel STING agonists. Further structure-activity relationship study and optimization led to the discovery of compound 45 as a highly potent human STING agonist with an EC 50 value of 1.2 nM. Compound 45 was found to bind to multiple human STING isoforms and accordingly activated the downstream TBK1/IRF3 and NF-κB signaling pathways in the reporter cells bearing with different STING isoforms. The activation on STING signaling pathway was abolished in the STING knock-out cells, indicating that it is a specific STING agonist. Compound 45 significantly inhibited the tumor growth in allograft 4T1 and CT26 tumor models by systemic administration, and more significantly, 45 was able to induce tumor regression in CT26 tumor model without inducing weight loss, suggesting that compound 45 is a highly promising candidate worthy for further development. [Display omitted] • A series of thieno [2,3-d]imidazole derivatives were designed as STING agonists. • 45 was able to activate h-STING isoforms and m-STING. • 45 was identified as a highly potent h-STING agonist with an EC 50 value of 1.2 nM. • Intravenous or intratumoral administration of 45 could inhibit tumor growth dramatically, without inducing weight loss. [ABSTRACT FROM AUTHOR]