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Cytidine acetylation yields a hypoinflammatory synthetic messenger RNA

  1. Author:
    Nance,Kellie
    Thalalla Gamage,Supuni
    Alam,Md Masud
    Yang,Acong
    Levy, Michaella J
    Link,Courtney
    Florens, Laurence
    Washburn, Michael P
    Gu,Shuo
    Oppenheim,Joost
    Meier,Jordan

  2. Author Address

    Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 538 Chandler Street, Frederick, MD 21702, USA., Laboratory of Cancer Immunometabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 538 Chandler Street, Frederick, MD 21702, USA., RNA Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 538 Chandler Street, Frederick, MD 21702, USA., Stowers Institute for Medical Research, Kansas City, MO 64110, USA., Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA., Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 538 Chandler Street, Frederick, MD 21702, USA. Electronic address: jordan.meier@nih.gov.,
    1. Year: 2022
    2. Date: Feb 17
    3. Epub Date: 2021 08 25
  2. Journal: Cell Chemical Biology
    1. 29
    2. 2
    3. Pages: 312-320.e7
  4. Type of Article: Article
  1. Abstract:

    Synthetic messenger RNA (mRNA) is an emerging therapeutic platform with important applications in oncology and infectious disease. Effective mRNA medicines must be translated by the ribosome but not trigger a strong nucleic acid-mediated immune response. To expand the medicinal chemistry toolbox for these agents, here we report the properties of the naturally occurring nucleobase N4-acetylcytidine (ac4C) in synthetic mRNAs. We find that ac4C is compatible with, but does not enhance, protein production in the context of synthetic mRNA reporters. However, replacement of cytidine with ac4C diminishes inflammatory gene expression in immune cells caused by synthetic mRNAs. Chemoproteomic capture indicates that ac4C alters the protein interactome of synthetic mRNAs, reducing binding to cytidine-binding proteins and an immune sensor. Overall, our studies illustrate the unique ability of ac4C to modulate RNA-protein interactions and provide a foundation for using N4-cytidine acylation to fine-tune the properties of nucleic acid therapeutics. Published by Elsevier Ltd.

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External Sources

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  2. DOI: 10.1016/j.chembiol.2021.07.003
  3. PMID: 35180432
  4. PII : S2451-9456(21)00313-5

Library Notes

  1. Fiscal Year: FY2021-2022
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