N1-Methylpseudouridine

N1-Methylpseudouridine (abbreviated m1Ψ) is a natural archaeal tRNA component[1] as well as a synthetic pyrimidine nucleoside used in biochemistry and molecular biology for in vitro transcription and is found in the SARS-CoV-2 mRNA vaccines tozinameran (Pfizer–BioNTech) and elasomeran (Moderna).[2]: 1 

N1-Methylpseudouridine
Names
IUPAC name
5-[(2S,3R,4S,5R)-3,4-Dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1-methylpyrimidine-2,4-dione
Other names
1-Methylpseudouridine; m1Ψ
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
UNII
  • InChI=1S/C10H14N2O6/c1-12-2-4(9(16)11-10(12)17)8-7(15)6(14)5(3-13)18-8/h2,5-8,13-15H,3H2,1H3,(H,11,16,17)/t5-,6-,7-,8+/m1/s1
    Key: UVBYMVOUBXYSFV-XUTVFYLZSA-N
  • O[C@H]1[C@@](O[C@H](CO)[C@H]1O)(C=2C(=O)NC(=O)N(C)C2)[H]
Properties
C10H14N2O6
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

Properties

N1-Methylpseudouridine is the methylated derivative of pseudouridine. It is used in in vitro transcription and for the production of RNA vaccines.[3][4] In vertebrates, it stimulates significantly less activation of the innate immune response compared to uridine,[5] while the translation is stronger.[6][7] In protein biosynthesis, it is read like uridine and enables comparatively high protein yields.[7][8] The nucleoside itself can be made by chemical methylation of pseudouridine.[9]

While pseudouridine can wobble-pair with bases other than A,[10] potentially leading to mistranslated proteins, it is unclear whether this happens with m1Ψ.[11][2]: 4 

History

In 2016, a protocol for large-scale synthesis of the nucleoside triphosphate from the ribonucleoside was published.[12]

In 2017–2018 it was tested in vaccines against Zika,[13][14][15] HIV-1,[15] influenza,[15] and Ebola.[16][2]: 5 

References
  1. Wurm JP, Griese M, Bahr U, Held M, Heckel A, Karas M, et al. (March 2012). "Identification of the enzyme responsible for N1-methylation of pseudouridine 54 in archaeal tRNAs". RNA. 18 (3): 412–420. doi:10.1261/rna.028498.111. PMC 3285930. PMID 22274954. In contrast, in most archaea this position is occupied by another hypermodified nucleotide: the isosteric N1-methylated pseudouridine
  2. Morais P, Adachi H, Yu YT (2021-11-04). "The Critical Contribution of Pseudouridine to mRNA COVID-19 Vaccines". Frontiers in Cell and Developmental Biology. 9: 789427. doi:10.3389/fcell.2021.789427. PMC 8600071. PMID 34805188.
  3. Knudson CJ, Alves-Peixoto P, Muramatsu H, Stotesbury C, Tang L, Lin PJ, et al. (September 2021). "Lipid-nanoparticle-encapsulated mRNA vaccines induce protective memory CD8 T cells against a lethal viral infection". Molecular Therapy. 29 (9): 2769–2781. doi:10.1016/j.ymthe.2021.05.011. PMC 8417516. PMID 33992803.
  4. Krienke C, Kolb L, Diken E, Streuber M, Kirchhoff S, Bukur T, et al. (January 2021). "A noninflammatory mRNA vaccine for treatment of experimental autoimmune encephalomyelitis". Science. 371 (6525): 145–153. Bibcode:2021Sci...371..145K. doi:10.1126/science.aay3638. PMID 33414215. S2CID 231138578.
  5. Nelson J, Sorensen EW, Mintri S, Rabideau AE, Zheng W, Besin G, et al. (June 2020). "Impact of mRNA chemistry and manufacturing process on innate immune activation". Science Advances. 6 (26): eaaz6893. Bibcode:2020SciA....6.6893N. doi:10.1126/sciadv.aaz6893. PMC 7314518. PMID 32637598.
  6. Andries O, Mc Cafferty S, De Smedt SC, Weiss R, Sanders NN, Kitada T (November 2015). "N(1)-methylpseudouridine-incorporated mRNA outperforms pseudouridine-incorporated mRNA by providing enhanced protein expression and reduced immunogenicity in mammalian cell lines and mice". Journal of Controlled Release. 217: 337–344. doi:10.1016/j.jconrel.2015.08.051. hdl:1854/LU-6993270. PMID 26342664.
  7. Svitkin YV, Cheng YM, Chakraborty T, Presnyak V, John M, Sonenberg N (June 2017). "N1-methyl-pseudouridine in mRNA enhances translation through eIF2α-dependent and independent mechanisms by increasing ribosome density". Nucleic Acids Research. 45 (10): 6023–6036. doi:10.1093/nar/gkx135. PMC 5449617. PMID 28334758.
  8. Parr CJ, Wada S, Kotake K, Kameda S, Matsuura S, Sakashita S, et al. (April 2020). "N 1-Methylpseudouridine substitution enhances the performance of synthetic mRNA switches in cells". Nucleic Acids Research. 48 (6): e35. doi:10.1093/nar/gkaa070. PMC 7102939. PMID 32090264.
  9. Earl RA, Townsend LB (June 1977). "A chemical synthesis of the nucleoside 1-methylpseudouridine". Journal of Heterocyclic Chemistry. 14 (4): 699–700. doi:10.1002/jhet.5570140437.
  10. Kierzek E, Malgowska M, Lisowiec J, Turner DH, Gdaniec Z, Kierzek R (March 2014). "The contribution of pseudouridine to stabilities and structure of RNAs". Nucleic Acids Research. 42 (5): 3492–3501. doi:10.1093/nar/gkt1330. PMC 3950712. PMID 24369424.
  11. Xia X (July 2021). "Detailed Dissection and Critical Evaluation of the Pfizer/BioNTech and Moderna mRNA Vaccines". Vaccines. 9 (7): 734. doi:10.3390/vaccines9070734. PMC 8310186. PMID 34358150. The replacement of uridine by N1-methylpseudourinine (Ψ) complicates some of these optimization processes because Ψ is more versatile in wobbling than U. … all U nucleotides were replaced by N1-methylpseudouridine (Ψ). However, Ψ wobbles more in base-pairing than U and can pair not only with A and G, but also, to a lesser extent, with C and U. … produce a longer protein of unknown fate with potentially deleterious effects.
  12. Shanmugasundaram M, Senthilvelan A, Kore AR (December 2016). "Gram-Scale Chemical Synthesis of Base-Modified Ribonucleoside-5'-O-Triphosphates". Current Protocols in Nucleic Acid Chemistry. 67: 13.15.1–13.15.10. doi:10.1002/cpnc.20. PMID 27911496. S2CID 5143935.
  13. Pardi N, Hogan MJ, Pelc RS, Muramatsu H, Andersen H, DeMaso CR, et al. (March 2017). "Zika virus protection by a single low-dose nucleoside-modified mRNA vaccination". Nature. 543 (7644): 248–251. Bibcode:2017Natur.543..248P. doi:10.1038/nature21428. PMC 5344708. PMID 28151488. we designed a potent anti-ZIKV vaccine … containing the modified nucleoside 1-methylpseudouridine (m1Ψ)
  14. Richner JM, Himansu S, Dowd KA, Butler SL, Salazar V, Fox JM, et al. (March 2017). "Modified mRNA Vaccines Protect against Zika Virus Infection". Cell. 168 (6): 1114–1125.e10. doi:10.1016/j.cell.2017.02.017. PMC 5388441. PMID 28222903. The mRNA was synthesized … where the UTP was substituted with 1-methylpseudoUTP
  15. Pardi N, Hogan MJ, Naradikian MS, Parkhouse K, Cain DW, Jones L, et al. (June 2018). "Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses". The Journal of Experimental Medicine. 215 (6): 1571–1588. doi:10.1084/jem.20171450. PMC 5987916. PMID 29739835. In this study, we characterize the immunogenicity of three vaccines consisting of m1Ψ-modified, FPLC-purified mRNA-LNPs encoding HIV-1 envelope (Env), ZIKV prM-E, and influenza virus hemagglutinin (HA)
  16. Meyer M, Huang E, Yuzhakov O, Ramanathan P, Ciaramella G, Bukreyev A (January 2018). "Modified mRNA-Based Vaccines Elicit Robust Immune Responses and Protect Guinea Pigs From Ebola Virus Disease". The Journal of Infectious Diseases. 217 (3): 451–455. doi:10.1093/infdis/jix592. PMC 5853918. PMID 29281112. Two mRNA vaccines were synthesized … where the UTP were substituted with 1-methylpseudo UTP
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.