期刊
CHEMBIOCHEM
卷 23, 期 8, 页码 -出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.202200005
关键词
cGAMP; imaging agents; STING pathway; fluorescent analogues; two-photon fluorescence lifetime imaging
资金
- Center of NanoScience Munich (CeNS)
- European Union [861381]
- Deutsche Forschungsgemeinschaft [RTG1721, TRR237, SFB1032, 201269156, PL 696/4-1]
- Projekt DEAL
- Marie Curie Actions (MSCA) [861381] Funding Source: Marie Curie Actions (MSCA)
The cGAS-STING pathway plays a crucial role in sensing cytosolic DNA. Research on the development of fluorescent moieties and synthesis of fluorescent molecules for detection is important for the therapeutic potential of this pathway.
The cGAS-STING pathway is known for its role in sensing cytosolic DNA introduced by a viral infection, bacterial invasion or tumorigenesis. Free DNA is recognized by the cyclic GMP-AMP synthase (cGAS) catalyzing the production of 2',3'-cyclic guanosine monophosphate-adenosine monophosphate (2',3'-cGAMP) in mammals. This cyclic dinucleotide acts as a second messenger, activating the stimulator of interferon genes (STING) that finally triggers the transcription of interferon genes and inflammatory cytokines. Due to the therapeutic potential of this pathway, both the production and the detection of cGAMP via fluorescent moieties for assay development is of great importance. Here, we introduce the paralleled synthetic access to the intrinsically fluorescent, cyclic dinucleotides 2'3'-c(th)GAMP and 3'3'-c(th)GAMP based on phosphoramidite and phosphate chemistry, adaptable for large scale synthesis. We examine their binding properties to murine and human STING and confirm biological activity including interferon induction by 2'3'-c(th)GAMP in THP-1 monocytes. Two-photon imaging revealed successful cellular uptake of 2'3'-c(th)GAMP in THP-1 cells.
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