Catalytic promiscuity of cGAS: A facile enzymatic synthesis of 2'-3' linked cyclic dinucleotides.

Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor that catalyzes the synthesis of cyclic GMP-AMP dinucleotide 2'3'-cGAMP. 2'3'-cGAMP functions as inducer for the production of type I interferons. Derivatives of this important second messenger are highly valuable for pharmaceutical applications. However, the production of these analogs requires complex, multistep synthesis. Herein, human cGAS is shown to react with a series of non-natural nucleotides, thus leading to novel cyclic dinucleotides. Most substrate derivatives were accepted with modifications at the nucleobase, ribose, as well as the α-thio phosphate. The presented results demonstrate the catalytic promiscuity of human cGAS and its utility for the biocatalytic synthesis of cyclic dinucleotide derivatives.