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N1-Methylpseudouridine

December 15, 2023

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
  • 13860-38-3 Y
3D model (JSmol)
  • Interactive image
ChEBI
  • CHEBI:19068
ChemSpider
  • 89930
  • 99543
UNII
  • 09RAD4M6WF
  • DTXSID50160724
  • 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).

Properties edit

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 [contradictory]

History edit

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 edit

  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. ^ a b c 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. ^ a b 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. ^ a b c 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

December 15, 2023
methylpseudouridine, abbreviated, m1Ψ, natural, archaeal, trna, component, well, synthetic, pyrimidine, nucleoside, used, biochemistry, molecular, biology, vitro, transcription, found, sars, mrna, vaccines, tozinameran, pfizer, biontech, elasomeran, moderna, n. N1 Methylpseudouridine abbreviated m1PS 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 NamesIUPAC name 5 2S 3R 4S 5R 3 4 Dihydroxy 5 hydroxymethyl oxolan 2 yl 1 methylpyrimidine 2 4 dioneOther names 1 Methylpseudouridine m1PSIdentifiersCAS Number 13860 38 3 Y3D model JSmol Interactive imageChEBI CHEBI 19068ChemSpider 89930PubChem CID 99543UNII 09RAD4M6WFCompTox Dashboard EPA DTXSID50160724InChI 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 s1Key UVBYMVOUBXYSFV XUTVFYLZSA NSMILES O C H 1 C O C H CO C H 1O C 2C O NC O N C C2 H PropertiesChemical formula C10H14N2O6Except where otherwise noted data are given for materials in their standard state at 25 C 77 F 100 kPa Infobox referencesProperties editN1 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 m1PS 11 2 4 contradictory History editIn 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 edit 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 a b c 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 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 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 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 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 a b Svitkin YV Cheng YM Chakraborty T Presnyak V John M Sonenberg N June 2017 N1 methyl pseudouridine in mRNA enhances translation through eIF2a dependent and independent mechanisms by increasing ribosome density Nucleic Acids Research 45 10 6023 6036 doi 10 1093 nar gkx135 PMC 5449617 PMID 28334758 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 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 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 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 PS complicates some of these optimization processes because PS is more versatile in wobbling than U all U nucleotides were replaced by N1 methylpseudouridine PS However PS 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 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 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 m1PS 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 a b c 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 m1PS modified FPLC purified mRNA LNPs encoding HIV 1 envelope Env ZIKV prM E and influenza virus hemagglutinin HA 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 Retrieved from https en wikipedia org w index php title N1 Methylpseudouridine amp oldid 1189940438, wikipedia, wiki, book, books, library,

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