Synthetic mRNA capping

Muttach, Fabian; Muthmann, Nils; Rentmeister, Andrea

doi:10.3762/bjoc.13.274

Cited by 73 publications

(85 citation statements)

References 123 publications

(132 reference statements)

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“…Besides stabilizing the mRNA in the translation, splicing, polyadenylation and nuclear exportation processes, cap0 protects the mRNA from exonucleases. Additionally, cap0 interacts with cap binding proteins (CBPs), essentials for the nuclear export of mRNA, and also with the translation initiation factor 4E (eIF4E) in the cytoplasm, crucial for the initiation of translation [11,25,26]. Moreover, it could be used as an innate immune marker, which differentiates the viral RNA from cellular RNA [26].…”

Section: ' Capmentioning

confidence: 99%

“…In recent years, human enzymes that form two other types of 5′ cap, cap1 and cap2, have been identified [26,27]. In these cases, the m7G-specific 2′O methyltransferase (2′O MTase) methylates the second or third ribonucleotide at the 2′O or 3′O position of the riboses generating cap1 and cap2 structures, respectively.…”

Section: ' Capmentioning

confidence: 99%

“…This process is simpler than the enzymatic capping, but it also presents some limitations. On the one hand, all mRNA molecules obtained are not capped, due to the competition between the cap analogue and the guanosine triphosphate (GTP), which is the initiator nucleotide [14,26]. As a consequence, the uncapped mRNAs are immediately digested by nucleases and can induce an immune response.…”

Section: ' Capmentioning

confidence: 99%

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Nanomedicines to Deliver mRNA: State of the Art and Future Perspectives

et al. 2020

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The use of messenger RNA (mRNA) in gene therapy is increasing in recent years, due to its unique features compared to plasmid DNA: Transient expression, no need to enter into the nucleus and no risk of insertional mutagenesis. Nevertheless, the clinical application of mRNA as a therapeutic tool is limited by its instability and ability to activate immune responses; hence, mRNA chemical modifications together with the design of suitable vehicles result essential. This manuscript includes a revision of the strategies employed to enhance in vitro transcribed (IVT) mRNA functionality and efficacy, including the optimization of its stability and translational efficiency, as well as the regulation of its immunostimulatory properties. An overview of the nanosystems designed to protect the mRNA and to overcome the intra and extracellular barriers for successful delivery is also included. Finally, the present and future applications of mRNA nanomedicines for immunization against infectious diseases and cancer, protein replacement, gene editing, and regenerative medicine are highlighted.

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Section: ' Capmentioning

confidence: 99%

Section: ' Capmentioning

confidence: 99%

Section: ' Capmentioning

confidence: 99%

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Nanomedicines to Deliver mRNA: State of the Art and Future Perspectives

et al. 2020

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“…In the last two decades, the synthesis of 5′‐capped RNAs has been achieved by following different routes based on enzymatic, chemical, or chemoenzymatic methods . Each strategy presents advantages and limitations, and, in particular, the production of 7m Gppp‐RNAs of defined sequences and in great amounts is a bottleneck for their use as tools for mechanistic and structural studies of the RNA world.…”

Section: Introductionmentioning

confidence: 99%

Combining Chemical Synthesis and Enzymatic Methylation to Access Short RNAs with Various 5′ Caps

et al. 2019

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Eukaryotic RNAs are heavily processed, including co‐ and post‐transcriptional formation of various 5′ caps. In small nuclear RNAs (snRNAs) or small nucleolar RNAs (snoRNAs), the canonical 7mG cap is hypermethylated at the N2‐position, whereas in higher eukaryotes and viruses 2′‐O‐methylation of the first transcribed nucleotide yields the cap1 structure. The function and potential dynamics of several RNA cap modifications have not been fully elucidated, which necessitates preparative access to these caps. However, the introduction of these modifications during chemical solid‐phase synthesis is challenging and enzymatic production of defined short and uniform RNAs also faces difficulties. In this work, the chemical synthesis of RNA is combined with site‐specific enzymatic methylation by using the methyltransferases human trimethylguanosine synthase 1 (hTgs1), trimethylguanosine synthase from Giardia lamblia (GlaTgs2), and cap methyltransferase 1 (CMTR1). It is shown that RNAs with di‐and trimethylated caps, as well as RNAs with caps methylated at the 2′‐O‐position of the first transcribed nucleotide, can be conveniently prepared. These highly modified RNAs, with a defined and uniform sequence, are hard to access by in vitro transcription or chemical synthesis alone.

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“…Because of the importance of the cap structure for mRNA stability and protein synthesis, there is a clear need for the development of novel tools for the analysis of mRNA cap metabolism [35]. Bednarek et al [36] invented several novel biotin-labelled cap analogues modified within the triphosphate bridge to increase their stability in cellular conditions.…”

Section: Introductionmentioning

confidence: 99%

5′ and 3′ modifications controlling RNA degradation: from safeguards to executioners

Gagliardi

Dziembowski

2018

Phil. Trans. R. Soc. B

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RNA degradation is a key process in the regulation of gene expression. In all organisms, RNA degradation participates in controlling coding and non-coding RNA levels in response to developmental and environmental cues. RNA degradation is also crucial for the elimination of defective RNAs. Those defective RNAs are mostly produced by ‘mistakes’ made by the RNA processing machinery during the maturation of functional transcripts from their precursors. The constant control of RNA quality prevents potential deleterious effects caused by the accumulation of aberrant non-coding transcripts or by the translation of defective messenger RNAs (mRNAs). Prokaryotic and eukaryotic organisms are also under the constant threat of attacks from pathogens, mostly viruses, and one common line of defence involves the ribonucleolytic digestion of the invader's RNA. Finally, mutations in components involved in RNA degradation are associated with numerous diseases in humans, and this together with the multiplicity of its roles illustrates the biological importance of RNA degradation. RNA degradation is mostly viewed as a default pathway: any functional RNA (including a successful pathogenic RNA) must be protected from the scavenging RNA degradation machinery. Yet, this protection must be temporary, and it will be overcome at one point because the ultimate fate of any cellular RNA is to be eliminated. This special issue focuses on modifications deposited at the 5′ or the 3′ extremities of RNA, and how these modifications control RNA stability or degradation. This article is part of the theme issue ‘5′ and 3′ modifications controlling RNA degradation’.

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Synthetic mRNA capping

Cited by 73 publications

References 123 publications

Nanomedicines to Deliver mRNA: State of the Art and Future Perspectives

Nanomedicines to Deliver mRNA: State of the Art and Future Perspectives

Combining Chemical Synthesis and Enzymatic Methylation to Access Short RNAs with Various 5′ Caps

5′ and 3′ modifications controlling RNA degradation: from safeguards to executioners

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