mRNA Vaccine and PseudoUridine

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The field of mRNA vaccines has rapidly developed during the pandemic. In order to reduce the immunogenicity of mRNA vaccines, the introduction of naturally modified nucleotides was used. PseudoUridine is the most abundant modified nucleoside in RNA, also known as the “fifth nucleoside.” The introduction of pseudoUridine or N1-methylpseudoUridine into mRNA can effectively reduce the immunogenicity caused by mRNA vaccines and enhance the stability of mRNA to promote protein expression further. As a result, the use of pseudoUridine or N1-methylpseudoUridine substitution will be the trend in mRNA vaccine production.

1. mRNA

In 1960, scientists confirmed the existence of mRNA molecules. mRNA is a messenger molecule that delivers genetic information carried by DNA in the nucleus to the ribosome in the cytoplasm, which directs protein synthesis. In this way, genetic information is translated into biological functions. 


mRNA circumvents the mutagenicity risk of DNA therapy mRNA controls timeliness well


mRNA is unable to diffuse across cell membranes mRNA is easily recognized and cleared by immune system

2. Modification of nucleosides

mRNA-triggered inflammations prompted researchers to test different sources of RNAs. Later in studies, researchers discovered that in tRNAs-modified nucleosides, replacing regular nucleosides with modified nucleosides attenuated mRNA inflammatory responses, as they were unable to activate TLR7 and TLR8.

3. From uridine to pseudoUridine/N1-methylpseudoUridine

Mechanistically, pseudoUridine is obtained from uridine through a base-specific isomerization reaction, i.e., pseudouridylation, in which the N-C glycosidic bond is substituted with the C-C bond. N1-methylpseudoUridine is produced through further methylation of pseudoUridine by Nep1, an N1- specific pseudoUridine methyltransferase. In 2005, a published article in Immunity indicated that replacing uridine with pseudoUridine can effectively prevent the activation of the immune response. Compared to mRNA containing unmodified uridine, mRNA containing pseudoUridine not only produced functional proteins in cell extracts and culture dishes but also enhanced protein production. Meanwhile, the drawback of pseudoUridine substitution is that it does not completely eliminate immune responses. However, this hindrance has withdrawn as the game-changer, N1- methylpseudoUridine, emerged in 2013. Conclusion In conclusion, pseudoUridine, an important part of mRNA vaccines, can Reduce mRNA activation in innate immunity Enhance mRNA stability Improve mRNA translation efficiency.

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