What is Pseudouridine and why is it important in mRNA Vaccines
Technical details of mRNA
What is Pseudouridine and why is it important in mRNA vaccines. Pseudouridine (abbreviated by the Greek letter psi- Ψ) is an isomer of the nucleoside uridine in which the uracil is attached via a carbon-carbon instead of a nitrogen-carbon glycosidic bond.
Pseudouridine is the most abundant RNA modification in cellular RNA. After transcription and following synthesis, RNA can be modified with over 100 chemically distinct modifications. These can potentially regulate RNA expression post-transcriptionally. In addition to the four standard nucleotides and play a variety of roles in the cell including translation, localization and stabilization of RNA. Pseudouridine is one of them. It is the C5-glycoside isomer of uridine that contains a C-C bond between C1 of the ribose sugar and C5 of uracil, rather than usual C1-N1 bond found in uridine. The C-C bond gives it more rotational freedom and conformational flexibility. In addition, pseudouridine has an extra hydrogen bond donor at the N1 position.
Also known as 5-ribosyluracil, pseudouridine is a ubiquitous constituent of structural RNA (transfer, ribosomal, small nuclear (snRNA) and small nucleolar), and present in coding RNA, across the three phylogenetic domains of life and was the first discovered.
Pseudouridine in rRNA and tRNA fine tunes and stabilize the RNA structure. This helps maintain their functions in mRNA decoding, ribosome assembly, processing and translation. Pseudouridine in snRNA has been shown to enhance spliceosomal RNA-pre-mRNA interaction to facilitate splicing regulation.
Technical Specs – This is what the Molecule Looks like
Molecule of Pseudouridine used in mRNA Vaccines
IUPAC Name 5-(β-D-Ribofuranosyl)pyrimidine-2,4(1H,3H)-dione
Other Names:
5-[(2S,3R,4S,5R)-3,4-Dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4(1H,3H)-dione
psi-Uridine, 5-Ribosyluracil, beta-D-Pseudouridine, 5-(beta-D-Ribofuranosyl)uracil
CAS Number 1445-07-5
Immunological use in Vaccines
Used in place of uridine in synthetic mRNA, pseudouridine in the modified mRNA molecule cause less inflammation response from Toll-like receptors. The TLR’s, a part of the human immune system that would otherwise identify the mRNA as unwelcome visitor in the human body. This makes pseudouridine useful in mRNA vaccines, including the mRNA COVID-19 vaccines. This property of pseudouridine discovered by Katalin Karikó and Drew Weissman in 2005. They they shared the 2023 Nobel Prize in Physiology or Medicine for this discovery.
N1-Methylpseudouridine provides even less innate immune response than Ψ, as well as improving translation capacity. Both Pfizer-BioNTech and Moderna mRNA vaccines therefore use N1-Methylpseudouridine rather than Ψ.
References:
2. Molecular Biology of the Gene by James Watson – explains the cell processes and use of tRNA, mRNA, rRNA.