9qvt
Crystal structure of STING CTD in complex with potent agonist D5
Structural highlights
FunctionSTING_HUMAN Facilitator of innate immune signaling that acts as a sensor of cytosolic DNA from bacteria and viruses and promotes the production of type I interferon (IFN-alpha and IFN-beta). Innate immune response is triggered in response to non-CpG double-stranded DNA from viruses and bacteria delivered to the cytoplasm. Acts by recognizing and binding cyclic di-GMP (c-di-GMP), a second messenger produced by bacteria, and cyclic GMP-AMP (cGAMP), a messenger produced in response to DNA virus in the cytosol: upon binding of c-di-GMP or cGAMP, autoinhibition is alleviated and TMEM173/STING is able to activate both NF-kappa-B and IRF3 transcription pathways to induce expression of type I interferon and exert a potent anti-viral state. May be involved in translocon function, the translocon possibly being able to influence the induction of type I interferons. May be involved in transduction of apoptotic signals via its association with the major histocompatibility complex class II (MHC-II). Mediates death signaling via activation of the extracellular signal-regulated kinase (ERK) pathway.[1] [2] [3] [4] [5] [6] [7] Publication Abstract from PubMedPharmacological activation of STING holds promise in cancer treatment. A recent trend is the development of tumour-specific or conditionally activated STING agonists for enhanced safety and efficacy. Here we explore an unconventional prodrug activation strategy for on-tumour synthesis of a potent agonist. Leveraging the unique mechanism of MSA2, a small-molecule agonist that dimerizes non-covalently before binding to STING, we showed that its analogues bearing reactive functional groups readily and selectively form covalent dimers under mild conditions and in complex environments. We identified a reacting pair that led to a thioether-linked dimer with submicromolar potency in cell-based assays. Caging one of the reactants with a self-immolative beta-glucuronide moiety resulted in a two-component prodrug system that near-exclusively formed the active compounds in tumours overexpressing beta-glucuronidase. These results exemplify the use of small-molecule recognition for on-site generation of active compounds from benign precursors. Tumour-specific STING agonist synthesis via a two-component prodrug system.,Hsu NS, Tang C, Mendes RV, Labao-Almeida C, Dos Reis CV, Coelho AR, Marques MC, Cabeza Cabrerizo M, Misteli R, Rooney TPC, Hyvonen M, Corzana F, Fior R, Bernardes GJL Nat Chem. 2025 Sep 16. doi: 10.1038/s41557-025-01930-9. PMID:40957952[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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