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

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      Author(s): † , † ,
      Publication date (Electronic):
      Journal: ACS Central Science
      Publisher: American Chemical Society

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          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.

          Abstract

          This article summarizes the development and function of N1-methylpseudouridine, an RNA modification used to increase the safety and efficacy of messenger RNA vaccines targeting COVID-19.

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          Most cited references68

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          Dynamic RNA Modifications in Gene Expression Regulation

          Molly E Evans, Ian A Roundtree, Tao Pan … (2017)
          Over 100 types of chemical modifications have been identified in cellular RNAs. While the 5' cap modification and the poly(A) tail of eukaryotic mRNA play key roles in regulation, internal modifications are gaining attention for their roles in mRNA metabolism. The most abundant internal mRNA modification is N6-methyladenosine (m6A), and identification of proteins that install, recognize, and remove this and other marks have revealed roles for mRNA modification in nearly every aspect of the mRNA life cycle, as well as in various cellular, developmental, and disease processes. Abundant noncoding RNAs such as tRNAs, rRNAs, and spliceosomal RNAs are also heavily modified and depend on the modifications for their biogenesis and function. Our understanding of the biological contributions of these different chemical modifications is beginning to take shape, but it's clear that in both coding and noncoding RNAs, dynamic modifications represent a new layer of control of genetic information.
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            Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19

            Yuan Huang, Chan Lon. Yang, Xin-feng Xu … (2020)
            Coronavirus disease 2019 is a newly emerging infectious disease currently spreading across the world. It is caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The spike (S) protein of SARS-CoV-2, which plays a key role in the receptor recognition and cell membrane fusion process, is composed of two subunits, S1 and S2. The S1 subunit contains a receptor-binding domain that recognizes and binds to the host receptor angiotensin-converting enzyme 2, while the S2 subunit mediates viral cell membrane fusion by forming a six-helical bundle via the two-heptad repeat domain. In this review, we highlight recent research advance in the structure, function and development of antivirus drugs targeting the S protein.
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              Where, When, and How: Context-Dependent Functions of RNA Methylation Writers, Readers, and Erasers

              Hailing Shi, Jiangbo Wei, Chuan Sheng He (2019)
              Cellular RNAs are naturally decorated with a variety of chemical modifications. The structural diversity of the modified nucleosides provides regulatory potential to sort groups of RNAs for organized metabolism and functions, thus affecting gene expression. Recent years have witnessed a burst of interest in and understanding of RNA modification biology, thanks to the emerging transcriptome-wide sequencing methods for mapping modified sites, highly-sensitive mass spectrometry for precise modification detection and quantification, and extensive characterization of the modification “effectors”, including enzymes (“writers” and “erasers”) that alter the modification level and binding proteins (“readers”) that recognize the chemical marks. However, challenges remain due to the vast heterogeneity in expression abundance of different RNA species, further complicated by divergent cell-type-specific and tissue-specific expression and localization of the effectors as well as modifications. In this review, we highlight recent progress in understanding the function of N 6 -methyladenosine (m 6 A), the most abundant internal mark on eukaryotic messenger RNA (mRNA), in light of the specific biological contexts of m 6 A effectors. We emphasize the importance of context for RNA modification regulation and function. RNA N 6 -methyladenosine (m 6 A) has emerged as a multifaceted controller for gene expression regulation, mediated through its effector proteins—writers, readers, and erasers. Shi et al . review recent advances in the mechanistic understandings of m 6 A effectors in various biological systems and cellular responses, emphasizing cellular and molecular contexts as important determinants of RNA modification functions.
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                Author and article information

                Journal
                Journal ID (nlm-ta): ACS Cent Sci
                Journal ID (iso-abbrev): ACS Cent Sci
                Journal ID (publisher-id): oc
                Journal ID (coden): acscii
                Title: ACS Central Science
                Publisher: American Chemical Society
                ISSN (Print): 2374-7943
                ISSN (Electronic): 2374-7951
                Publication date (Electronic): 06 April 2021
                Electronic Location Identifier: acscentsci.1c00197
                Affiliations
                [† ]Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health , 538 Chandler Street, Frederick, Maryland 21702, United States
                Author notes
                Article
                DOI: 10.1021/acscentsci.1c00197
                PMC ID: 8043204
                PubMed ID: 34075344
                SO-VID: f2c59435-c788-4b27-9b75-e658d6f4221d
                Copyright © Not subject to U.S. Copyright. Published 2021 by American Chemical Society
                License:

                This article is made available via the PMC Open Access Subset for unrestricted RESEARCH re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                Date received : 10 February 2021
                Categories
                Subject: Outlook
                Custom metadata
                document-id-old-9 oc1c00197
                document-id-new-14 oc1c00197
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