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Cited by 91RNA and protein synthesis mechanismsDNA and Nucleic Acid ChemistryRNA Interference and Gene Delivery

Chemical Modifications of mRNA Ends for Therapeutic Applications

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Warminski, Marcin, Mamot, Adam, Depaix, Anaïs, Kowalska, Joanna, Jemielity, Jacek·2023·Accounts of Chemical Research
DOI 10.1021/acs.accounts.3c00442PMC PMC10586375
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Abstract

Messenger ribonucleic acid (mRNA) is the universal cellular instruction for ribosomes to produce proteins. Proteins are responsible for most of the functions of living organisms, and their abnormal structure or activity is the cause of many diseases. mRNA, which is expressed in the cytoplasm and, unlike DNA, does not need to be delivered into the nucleus, appears to be an ideal vehicle for pursuing the idea of gene therapy in which genetic information about proteins is introduced into an organism to exert a therapeutic effect. mRNA molecules of any sequence can be synthesized using the same set of reagents in a cell-free system via a process called in vitro transcription (IVT), which is very convenient for therapeutic applications. However, this does not mean that the path from the idea to the first mRNA-based therapeutic was short and easy. It took 30 years of trial and error in the search for solutions that eventually led to the first mRNA vaccines created in record time during the SARS-CoV-2 pandemic. One of the fundamental problems in the development of RNA-based therapeutics is the legendary instability of mRNA, due to the transient nature of this macromolecule. From the chemical point of view, mRNA is a linear biopolymer composed of four types of ribonucleic subunits ranging in length from a few hundred to hundreds of thousands of nucleotides, with unique structures at its ends: a 5'-cap at the 5'-end and a poly(A) tail at the 3'-end. Both are extremely important for the regulation of translation and mRNA durability. These elements are also convenient sites for sequence-independent labeling of mRNA to create probes for enzymatic assays and tracking of the fate of mRNA in cells and living organisms. Synthetic 5'-cap analogs have played an important role in the studies of mRNA metabolism, and some of them have also been shown to significantly improve the translational properties of mRNA or affect mRNA stability and reactogenicity. The most effective of these is used in clinical trials of mRNA-based anticancer vaccines. Interestingly, thanks to the knowledge gained from the biophysical studies of cap-related processes, even relatively large modifications such as fluorescent tags can be attached to the cap structure without significant effects on the biological properties of the mRNA, if properly designed cap analogs are used. This has been exploited in the development of molecular tools (fluorescently labeled mRNAs) to track these macromolecules in complex biological systems, including organisms. These tools are extremely valuable for better understanding of the cellular mechanisms involved in mRNA metabolism but also for designing therapeutic mRNAs with superior properties. Much less is known about the usefulness/utility of poly(A) tail modifications in the therapeutic context, but it is clear that chemical modifications of poly(A) can also affect biochemical properties of mRNA. This Account is devoted to chemical modifications of both the 5'- and 3'-ends of mRNA aimed at improving the biological properties of mRNA, without interfering with its translational function, and is based on the authors' more than 20 years of experience in this field.

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  • The CleanCap AG trinucleotide cap analog is used in the Pfizer-BioNTech vaccine.

    “we also evaluated the translatability of three mRNAs harboring the CleanCap AG trinucleotide cap analog used in the Pfizer-BioNTech vaccine.37,38”

    From Evaluation of synthetic mRNA with selected UTR sequences and alternative poly(A) tail, in vitro and in vivo (2025) · cites this paper as [37]

    The “How to Cap RNA” section says trinucleotide cap analogs are sold as CleanCap reagents and that a modified trinucleotide cap was used to produce the Comirnaty vaccine. It does not identify that vaccine cap as CleanCap AG, so the specific product attribution is unsupported. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Warminski, M., Mamot, A., Depaix, A., Kowalska, J., & Jemielity, J.
Affiliations
  • Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, Pasteura 5, 02-093 Warsaw, Poland
  • University of Warsaw (PL)
Corresponding author
  • Kowalska, Joanna
  • Jemielity, Jacek
ORCID
Venue
Accounts of Chemical Research
Publisher
American Chemical Society (ACS)
Published
2023-10-02
Volume
56
Issue
20
Pages
2814-2826
ISSN
  • 0001-4842 (ISSN-L)
  • 1520-4898
DOI
10.1021/acs.accounts.3c00442
PMC
PMC10586375
OpenAlex
W4387242059
Cited by
91
References
12
Citations by year
2026: 24 · 2025: 38 · 2024: 28 · 2023: 1
FWCI
7.87
Type
journal article
Language
en
Open access
Licence
Locations
  • Accounts of Chemical Research (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
Narodowe Centrum Nauki (2018/31/B/ST5/03821, 2019/33/B/ST4/01843, 2022/47/D/ST4/00386)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Keywords
mRNA 5' cap, poly(A) tail, mRNA stability, mRNA vaccines, mRNA therapeutics, in vitro transcription, mRNA metabolism, mRNA translation, COVID-19 vaccines
MeSH terms
COVID-19, SARS-CoV-2, Humans, Ribosomes, RNA, Messenger, Protein Biosynthesis

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