![]() ![]() For example, the binding affinity of IFIT-1 (an interferon Induced protein) for Cap 1 and Cap 2 is much weaker than for 5’ triphosphate or Cap 0 RNAs, and IFIT-1 binding to non-2’-O methylated RNAs competes with the translational initiation factor EIF4E (shown here) to prevent translation. Cap 1 methylation has been shown to modulate binding or activation of innate immune sensors. Many of these viruses are attenuated when their methyltransferases are inactivated, suggesting that cap structure may play an important role in self vs. This is an Open Access article under the CC BY license.Īccording to McCaffrey and collaborators, cytoplasmic viruses frequently possess mechanisms to acquire a Cap 1 structure. Taken from McCaffrey and collaborators and free to use. The presence of 2’-O-methyl groups at R 1 and R 2 determine whether a cap structure is Cap 0, Cap 1, and Cap 2, as indicated. In humans and other higher eukaryotes, the 2’ ribose position of the first cap-proximal nucleotide is methylated to form a Cap 1 structure, and, in ~50% of transcripts, the second cap-proximal nucleotide is 2’ O-methylated to form Cap 2 (see Furuichi and Shatkin). Cap 0 is important for the recruitment of translational initiation factors, and it prevents degradation of the mRNA. These RNAs can have several forms, as depicted here. ![]() (2019) provide in-depth discussions and references regarding the biological relevance of these mRNA regions, brief synopses of which are provided in the following subsections.Ĭap Structure: Eukaryotic RNAs are 5’ capped with a 7-methylguanosine (m7G) connected by a 5’-to-5’ triphosphate bridge to the first nucleotide. Depicted here, these regions include 5’ cap structure, 5’ untranslated region (UTR), open reading frame (ORF), 3’ UTR, and poly(A) tail. Overview of the Biological Relevance of mRNA Structureīefore discussing current strategies for the optimization of IVT mRNA sequence in the context of vaccine prophylaxis or therapy, it is helpful to first consider what we know about the biological function of the various structural regions of mRNA. As a final note, this blog is intended to be a timely primer, if you will, for the upcoming TriLink webinar on Optimizing Your mRNA Coding Sequence. In keeping with the intent and scope of individual Zone blogs, short synopses of selected aspects of IVT mRNA sequence optimization will be presented, along with lead references to the original publications or reviews that can be consulted for additional information or technical details. PubMed search query ((optimization) OR (engineering)) AND ("mRNA sequence") and chart by Jerry Zon showing the linear forecast (dashed line). This topic has been trending upwards in recent years, as indicated by the linear forecast dashed line shown in this chart reports found by word searching the NIH PubMed database for 2013 – 2020. This blog provides some perspective on published strategies for this type of sequence optimization, which is alternatively referred to sequence engineering. ![]() The previous Zone blog (April 27, 2021) titled mRNA Vaccines – A New Era in Vaccinology, emphasized that mRNA sequence optimization is needed to achieve efficient intracellular translation of the encoded protein antigens, as well as to minimize undesired innate immunogenicity due to RNA structural elements. TriLink Technologies Contributes to These Advances.Keys Are 5’ Capping, Codon Optimization, and Modified Bases.Sequence Optimization of IVT mRNA Has Benefited COVID-19 Vaccines. ![]()
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