Nucleoside-modified messenger RNA

Source: Wikipedia, the free encyclopedia.

A nucleoside-modified messenger RNA (modRNA) is a synthetic

mRNA vaccines, of which the first authorized were COVID-19 vaccines (such as Comirnaty and Spikevax
).

Background

A ribosome (depicted in green) creates a protein (depicted here as a string of beads representing amino acids) encoded in an mRNA (depicted as a ribbon of nucleotides) that may be modified to reduce inflammation in the cell.

mRNA is produced by synthesising a ribonucleic acid (RNA) strand from nucleotide building blocks according to a deoxyribonucleic acid (DNA) template, a process that is called transcription.[2] When the building blocks provided to the RNA polymerase include non-standard nucleosides such as pseudouridine — instead of the standard adenosine, cytidine, guanosine, and uridine nucleosides — the resulting mRNA is described as nucleoside-modified.[3]

Production of protein begins with assembly of ribosomes on the mRNA, the latter then serving as a blueprint for the synthesis of proteins by specifying their amino acid sequence based on the genetic code in the process of protein biosynthesis called translation.[4]

Overview

To induce cells to make proteins that they do not normally produce, it is possible to introduce

TNF-alpha, and when sufficiently intense lead to programmed cell death.[6]

The inflammatory nature of exogenous RNA can be masked by modifying the nucleosides in mRNA.

secondary structure of the mRNA, which can reduce recognition by the innate immune system while still allowing effective translation.[9]

Significance of untranslated regions

A normal mRNA starts and ends with sections that do not code for amino acids of the actual protein. These sequences at the 5′ and 3′ ends of an mRNA strand are called untranslated regions (UTRs). The two UTRs at their strand ends are essential for the stability of an mRNA and also of a modRNA as well as for the efficiency of translation, i.e. for the amount of protein produced. By selecting suitable UTRs during the synthesis of a modRNA, the production of the target protein in the target cells can be optimised.[5][12]

Delivery

Comparing uptake of RNA and modRNA by the cell

Various difficulties are involved in the introduction of modRNA into certain target cells. First, the modRNA must be protected from ribonucleases.[5] This can be accomplished, for example, by wrapping it in liposomes. Such "packaging" can also help to ensure that the modRNA is absorbed into the target cells. This is useful, for example, when used in vaccines, as nanoparticles are taken up by dendritic cells and macrophages, both of which play an important role in activating the immune system.[13]

Furthermore, it may be desirable that the modRNA applied is introduced into specific body cells. This is the case, for example, if

coronary artery.[14]

Applications

An important field of application are mRNA vaccines.

Replacing uridine with pseudouridine to evade the innate immune system was pioneered by Karikó and Weissman in 2005.[15][16] They won the 2023 Nobel Prize in Physiology or Medicine as a result of their work.[17]

Another milestone was achieved by demonstrating the life-saving efficacy of nucleoside modified mRNA in a mouse model of a lethal lung disease by the team of Kormann and others in 2011.[18]

N1-methyl-pseudouridine was used in vaccine trials against

Ebola[22] in 2017–2018.[23]
: 5 

The first authorized for use in humans were

codon optimization to minimize the presence of uridine. This vaccine is less effective, however.[35][16]

Other possible uses of modRNA include the regeneration of damaged heart muscle tissue,[36][37] an enzyme-replacement tool[38] and cancer therapy.[39][40]

References

  1. PMID 25301935
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  2. ^ Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P (2002). From DNA to RNA (4 ed.). Garland Science.
  3. PMID 27987145.{{cite book}}: CS1 maint: location missing publisher (link
    )
  4. ^ Lodish H, Berk A, Zipursky SL, Matsudaira P, Baltimore D, Darnell J (2000). The Three Roles of RNA in Protein Synthesis (4th ed.). New York: W. H. Freeman. pp. Sec 4.4.
  5. ^
    PMID 23064118
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  6. PMID 22617878
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  7. PMID 16111635
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  8. PMID 26342664
    .
  9. ^
    PMID 28334758
    .
  10. PMID 26578598
    .
  11. PMID 22274954
    . In contrast, in most archaea this position is occupied by another hypermodified nucleotide: the isosteric N1-methylated pseudouridine.
  12. PMID 30638957
    .
  13. PMID 24295808
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  14. PMID 30038937
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  15. PMID 16111635
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  16. ^
    S2CID 237515383
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  17. ^ "The Nobel Prize in Physiology or Medicine 2023".
  18. S2CID 205275040
    .
  19. PMID 28151488
    . we designed a potent anti-ZIKV vaccine … containing the modified nucleoside 1-methylpseudouridine (m1Ψ)
  20. PMID 28222903
    . The mRNA was synthesized … where the UTP was substituted with 1-methylpseudoUTP
  21. ^
    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)
  22. PMID 29281112
    . Two mRNA vaccines were synthesized … where the UTP were substituted with 1-methylpseudo UTP
  23. PMID 34805188
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  24. ^ "Pfizer and BioNTech Celebrate Historic First Authorization in the U.S. of Vaccine to Prevent COVID-19". www.businesswire.com. 12 December 2020.
  25. S2CID 228087117
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  26. ^ Hohmann-Jeddi C (2020-11-10). "Hoffnungsträger BNT162b2: Wie funktionieren mRNA-Impfstoffe?". Pharmazeutische Zeitung (in German). Retrieved 2020-11-28.
  27. S2CID 221476409
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  28. S2CID 221589144
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  29. ^ "Conditions of Authorisation for Pfizer/BioNTech COVID-19 Vaccine" (Decision). Medicines & Healthcare Products Regulatory Agency. 8 December 2020.
  30. FDA
    .
  31. S2CID 221887746
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  32. ^ "Moderna's Pipeline". Moderna. Retrieved 2020-11-28.
  33. S2CID 227176634
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  34. ^ "COVID-19". CureVac. Retrieved 2020-12-21.
  35. S2CID 235480198
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  36. PMID 32822006
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  37. PMID 24013197
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  38. PMID 37607539
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  39. PMID 26665011
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  40. S2CID 20794075
    .

Further reading

Scholia has a profile for nucleoside-modified messenger RNA (Q103194381).
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