N1-Methylpseudouridine

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(Redirected from
1-methyl-3'-pseudouridylyl
)
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).

N1-Methylpseudouridine (abbreviated m1Ψ) is a natural

elasomeran (Moderna).[2]

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] work examining COVID-19 modRNA vaccines that replace all their uridines with N1-methylpseudouridine show faithful protein production.[11]

More recent work from Mulroney and colleagues has identified that N1-methylpseudouridine can give rise to slippery sequences that promote ribosomal frameshifting.

Vaxzevria (Oxford–AstraZeneca), despite the latter not demonstrating meaningful production of frameshifted sequences. In human donors, the degree of recognition of frameshifted peptides by T cells varies greatly, suggesting that the extent to which frameshifting occurs may vary greatly as well. Importantly, frameshifted products are rare but well-defined events in protein production, including in viral infections, and can give rise to sequences that can be targeted by the immune system.[13][14] Furthermore, despite significant disparity at the level of nucleotide sequences between COVID-19 vaccines from Pfizer/BioNTech and Moderna,[15] the safety profile of both vaccines is comparable,[16]
arguing against any meaningful effect of frameshifting on the safety profile of the vaccines.

History

In 2016, a protocol for large-scale synthesis of the nucleoside triphosphate from the ribonucleoside was published.[17]

In 2017–2018 it was tested in vaccines against

Ebola.[21][2]
: 5 

References

  1. PMID 22274954
    . In contrast, in most archaea this position is occupied by another hypermodified nucleotide: the isosteric N1-methylated pseudouridine
  2. ^
    PMID 34805188
    .
  3. PMID 33992803
    .
  4. S2CID 231138578
    .
  5. PMID 32637598
    .
  6. PMID 26342664
    .
  7. ^
    PMID 28334758
    .
  8. PMID 32090264
    .
  9. doi:10.1002/jhet.5570140437
    .
  10. PMID 24369424
    .
  11. PMID 35988540
    .
  12. PMID 38057663
    .
  13. S2CID 260829874
    .
  14. PMID 20038640
    .
  15. PMID 37821446
    .
  16. PMID 35696161
    .
  17. S2CID 5143935
    .
  18. PMID 28151488
    . we designed a potent anti-ZIKV vaccine … containing the modified nucleoside 1-methylpseudouridine (m1Ψ)
  19. PMID 28222903
    . The mRNA was synthesized … where the UTP was substituted with 1-methylpseudoUTP
  20. ^
    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)
  21. PMID 29281112
    . Two mRNA vaccines were synthesized … where the UTP were substituted with 1-methylpseudo UTP
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