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Modifications in an Emergency: The Role of N1-Methylpseudouridine in COVID-19 Vaccines.

ABSTRACT: The novel coronavirus SARS-CoV-2, the cause of the COVID-19 pandemic, has inspired one of the most efficient vaccine development campaigns in human history. A key aspect of COVID-19 mRNA vaccines is the use of the modified nucleobase N1-methylpseudouridine (m1Ψ) to increase their effectiveness. In this Outlook, we summarize the development and function of m1Ψ in synthetic mRNAs. By demystifying how a novel element within these medicines works, we aim to foster understanding and highlight future opportunities for chemical innovation.

SUBMITTER: Nance KD

PROVIDER: S-EPMC8043204 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Modifications in an Emergency: The Role of N1-Methylpseudouridine in COVID-19 Vaccines.

Nance Kellie D KD Meier Jordan L JL

ACS central science 20210406 5

The novel coronavirus SARS-CoV-2, the cause of the COVID-19 pandemic, has inspired one of the most efficient vaccine development campaigns in human history. A key aspect of COVID-19 mRNA vaccines is the use of the modified nucleobase N1-methylpseudouridine (m1Ψ) to increase their effectiveness. In this Outlook, we summarize the development and function of m1Ψ in synthetic mRNAs. By demystifying how a novel element within these medicines works, we aim to foster understanding and highlight future ...[more]

PMID: 34075344

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N1-methylpseudouridine found within COVID-19 mRNA vaccines produces faithful protein products

Project description:Given the interest in the COVID mRNA vaccines, we sought to investigate how the RNA modification N1-methylpseudouridine (and its related modification, pseudouridine) is read by ribosomes and reverse transcriptases. By looking at reverse transcriptase data, we can gain information on how the modification affects duplex stability, which may have important consequences for the tRNA-mRNA interactions found in the ribosome.

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N1-methylpseudouridine found within COVID-19 mRNA vaccines produces faithful protein products.

Project description:Synthetic mRNA technology is a promising avenue for treating and preventing disease. Key to the technology is the incorporation of modified nucleotides such as N1-methylpseudouridine (m1Ψ) to decrease immunogenicity of the RNA. However, relatively few studies have addressed the effects of modified nucleotides on the decoding process. Here, we investigate the effect of m1Ψ and the related modification pseudouridine (Ψ) on translation. In a reconstituted system, we find that m1Ψ does not significantly alter decoding accuracy. More importantly, we do not detect an increase in miscoded peptides when mRNA containing m1Ψ is translated in cell culture, compared with unmodified mRNA. We also find that m1Ψ does not stabilize mismatched RNA-duplex formation and only marginally promotes errors during reverse transcription. Overall, our results suggest that m1Ψ does not significantly impact translational fidelity, a welcome sign for future RNA therapeutics.

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N1-methylpseudouridine found within COVID-19 mRNA vaccines produces faithful protein products

Project description:The COVID mRNA vaccines utilize the modified nucleobase N1-methylpseudouridine, in place of canonical uridine, to improve immunogenicity and protein yield. However, relatively few studies have investigated the effect of modified nucleobases on the fidelity of protein translation. Given the interest in the COVID mRNA vaccines, we sought to investigate how N1-methylpseudouridine (and the related modification pseudouridine) is read by ribosomes.

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N1-Methylpseudouridine and pseudouridine modifications modulate mRNA decoding during translation.

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N1-methylpseudouridine found within COVID-19 mRNA vaccines produces faithful protein products

Project description:N1-methylpseudouridine found within COVID-19 mRNA vaccines produces faithful protein products

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N1-Methylpseudouridine and pseudouridine modifications modulate mRNA decoding during translation

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Influence of N1-Methylpseudouridine in Guide RNAs on CRISPR/Cas9 Activity.

Project description:At present, there are many strategies to improve the activity of CRISPR/Cas9. A well-known and effective approach is guide RNA modification. Many chemical guide RNA modifications have been studied, whereas naturally occurring RNA modifications are largely unexplored. N1-methylpseudouridine (m1Ψ) is an RNA base modification widely used in mRNA therapy, and it holds great promise for application in genome editing systems. The present study focuses on investigating the effect of N1-methylpseudouridine on the functioning of CRISPR/Cas9. In vitro cleavage assays helped determine the level of m1Ψ guide RNA modification that is sufficient to cleave the target substrate. By analyzing FAM-labeled dsDNA substrate cleavage, we calculated the kinetic parameters and the specificity scores of modified guide RNAs. Neon transfection and digital PCR enabled us to assess the activity of modified guide RNAs in mammalian cells. Our study shows that the presence of m1Ψ in guide RNAs can help preserve on-target genome editing while significantly reducing the off-target effects of CRISPR/Cas9 in vitro. We also demonstrate that Cas9 complexes with guide RNAs containing m1Ψ allow for genome editing in human cells. Thus, the incorporation of m1Ψ into guide RNAs supports CRISPR/Cas9 activity both in vitro and in cells.

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Project description: Not available

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Pseudouridine and N1-Methylpseudouridine Display pH-Independent Reaction Rates with Bisulfite Yielding Ribose Adducts.

Project description:In RNA, pseudouridine (Ψ) and 5-methylcytidine (m5C) are located by their differential reactions with NaHSO3 at pH 5. The pyrimidines were allowed to react with NaHSO3, NaN3, NaCN, or NaSCN at pH 5 to find that NaHSO3 was unique in achieving quantitative yields. Pseudouridine reaction selectivity with NaHSO3 was found at pH 7 supported by the reaction rate constants. The Ψ derivative N1-methylpseudouridine found in mRNA vaccines reacts similarly with bisulfite to yield ribose adducts.

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