@article {572326,
	title = {Hydrolysis of 2{\textquoteright}3{\textquoteright}-cGAMP by ENPP1 and design of nonhydrolyzable analogs.},
	journal = {Nat Chem Biol},
	volume = {10},
	number = {12},
	year = {2014},
	month = {2014 Dec},
	pages = {1043-8},
	abstract = {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{\textquoteright}3{\textquoteright}-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{\textquoteright}3{\textquoteright}-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{\textquoteright}3{\textquoteright}-cGAMP (2{\textquoteright}3{\textquoteright}-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{\textquoteright}3{\textquoteright}-cG(s)A(s)MP is therefore improved over natural 2{\textquoteright}3{\textquoteright}-cGAMP as a model agonist and has potential as a vaccine adjuvant and cancer therapeutic.},
	keywords = {Animals, Antineoplastic Agents, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Humans, Hydrolysis, Interferon-beta, Membrane Proteins, Mice, Monocytes, Nucleotides, Cyclic, Organothiophosphorus Compounds, Phosphoric Diester Hydrolases, Pyrophosphatases, Recombinant Proteins, Second Messenger Systems, Signal Transduction},
	issn = {1552-4469},
	doi = {10.1038/nchembio.1661},
	author = {Li, Lingyin and Yin, Qian and Kuss, Pia and Maliga, Zoltan and Mill{\'a}n, Jos{\'e} L and Wu, Hao and Mitchison, Timothy J.}
}
