5-Methylcytidine-5'-Triphosphate

Description

RNA methylation signals a plethora of cellular functions including biochemical and metabolic stabilization of RNA, immune response, resistance to antibiotics, mRNA reading frame maintenance, splicing and more. Methylation of the 5 position of cytidine is a common, post-transcriptional modification in a number of RNA species, such as mRNA, miRNA and tRNA. 5-Methylcytidine-5'-Triphosphate (5-Methyl-CTP) is a modified nucleoside triphosphate employed to impart desirable characteristics such as increased nuclease stability, increased translation or reduced interaction of innate immune receptors with in vitro transcribed RNA. 5-Methyl-CTP, as well as Pseudo-UTP and 2-Thio-UTP, have been shown to reduce innate immune stimulation in culture and in vivo while enhancing translation in recent publications by Kormann et al. and Warren et al. Kormann et al. demonstrated the improvement of therapeutic mRNA in vivo delivery by chemical modification. Chemical modifications explored included Pseudo-U, N6-Methyl-A, 2-Thio-U and 5-Methyl-C. The team found that by substituting 25% of the uridine and cytidine with 2-Thio-U and 5-Methyl-C respectively, they were able to significantly decrease toll-like receptor (TLR) mediated recognition of the mRNA in mice. By reducing the activation of the innate immune system, these modifications also increase the stability and longevity of the mRNA in vivo. Warren et al. determined an efficient means of reprogramming multiple human cell types using modified mRNA that can express the four primary reprogramming proteins. These cells are referred to as induced pluripotency stem cells (iPSCs). Warren et al. found that enzymatically synthesized RNA employing 5-Methyl-CTP, Pseudo-UTP and ARCA effectively evaded the cell's antiviral response, a crucial component in their success.This reduced toxicity associated with repeated transfection with in vitro transcribed mRNA.

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