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Hydrolysis of 2'3'-cGAMP by ENPP1 and design of nonhydrolyzable analogs.
MedLine Citation:
PMID:  25344812     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Agonists of mouse STING (TMEM173) shrink and even cure solid tumors by activating innate immunity; human STING (hSTING) agonists are needed to test this therapeutic hypothesis in humans. The endogenous STING agonist is 2'3'-cGAMP, a second messenger that signals the presence of cytosolic double-stranded DNA. We report activity-guided partial purification and identification of ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP1) to be the dominant 2'3'-cGAMP hydrolyzing activity in cultured cells. The hydrolysis activity of ENPP1 was confirmed using recombinant protein and was depleted in tissue extracts and plasma from Enpp1(-/-) mice. We synthesized a hydrolysis-resistant bisphosphothioate analog of 2'3'-cGAMP (2'3'-cG(s)A(s)MP) that has similar affinity for hSTING in vitro and is ten times more potent at inducing IFN-β secretion from human THP1 monocytes. Studies in mouse Enpp1(-/-) lung fibroblasts indicate that resistance to hydrolysis contributes substantially to its higher potency. 2'3'-cG(s)A(s)MP is therefore improved over natural 2'3'-cGAMP as a model agonist and has potential as a vaccine adjuvant and cancer therapeutic.
Authors:
Lingyin Li; Qian Yin; Pia Kuss; Zoltan Maliga; José L Millán; Hao Wu; Timothy J Mitchison
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-10-26
Journal Detail:
Title:  Nature chemical biology     Volume:  -     ISSN:  1552-4469     ISO Abbreviation:  Nat. Chem. Biol.     Publication Date:  2014 Oct 
Date Detail:
Created Date:  2014-10-26     Completed Date:  -     Revised Date:  2014-10-27    
Medline Journal Info:
Nlm Unique ID:  101231976     Medline TA:  Nat Chem Biol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Data Bank Information
Bank Name/Acc. No.:
PubChem-Substance/209523873;  209523874;  209523875;  209523876;  209523877;  209523878
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