Recent Advances in Synthesis and Biological Activity of Modified Cap Analogs

The recent explosion in mRNA cap analogs underscores the importance of mRNA as a powerful tool in the study of RNA metabolism and highlights the potential of targeting mRNA for the treatment of cancer, gene therapy, antiviral therapy and improvement of the localization of nuclease-targeting drugs. The chemically modified mRNA cap analogs consist of a unique cap structure, m(7)G[5'] ppp[5'] N (where N = G, A, C or U), present at the 5'-end of many eukaryotic cellular and viral RNAs and several non-coding RNAs. The presence of sugar substitution on m(7)G moiety of cap analog has had a great impact on the nature of the orientation, translational efficiency, binding affinity and nuclear stability. It is noteworthy that these modified cap analogs are classified as anti-reverse cap analog (ARCA) that incorporates into mRNA exclusively in the forward orientation. This review focuses on the recent development in the synthesis of various cap analogs with modifications on 7-methylguanosine (m(7)G) sugar substitution such as 3'-propargyl, 2', 3'-isopropylidene, 2', 3'-diacetyl and 2'-amino, triphosphate bridging such as imidodiphosphate and methylenebis(phosphonate), triphosphate non-bridging such as BH3, Se and S, and nucleobase substitution such as 6-thioguanosine and triazole. In addition, the biological applications of these novel cap analogs are discussed.