Metazoan second messenger 2’3’-cGAMP, produced by DNA-activated cGAS, is a cyclic dinucleotide (CDN) that binds to and activates the ER-transmembrane adaptor protein STING, ultimately inducing secretion of type I interferons and immune system activation. This discovery has led to intense interest in CDNs as potential vaccine adjuvants and immunotherapeutics. The conversion of ATP and GTP into 2’,3’-cGAMP by cGAMP synthase (cGAS) represents an impressive biocatalytic synthesis of a complex molecule. In the field of CDN biocatalysis, we have discovered a late stage derivatization of 2’3’-cGAMP to 2’3’-cGIMP via a highly efficient adenosine monophosphate deaminase (AMPDA) deamination. This biocatalytic transformation offers a substantial efficiency advantage over typical lengthy chemical synthetic routes to CDNs. Separately, we have also developed a novel biocatalytic method employing snake venom phosphodiesterase (svPDE) and nuclease P1 (nP1) and successfully applied it to stereochemistry determination of 2’3’-cGAMP bisphosphorothioates (2’3’-cGSASMP). This method unambiguously assigned the phosphorothioate stereochemistry of the four diastereomers of 2’3’-cGSASMP. The scope of reactivity and specificity of AMPDA, and regio- and stereo-specificity of svPDE and nP1 toward 2’3’−cyclic dinucleotide bisphosphorothioates (2’3’−CDNSS) will be presented.

Novel applications of biocatalysis to late stage derivatization and stereochemistry determination of 2’3’−cyclic dinucleotide bisphosphorothioates

2019 Spring National Meeting

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