Cryo-EM and antisense targeting of the 28-kDa frameshift stimulation element from the SARS-CoV-2 RNA genome

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  • Zhang, Kaiming
    • Other Affiliation: Stanford University
  • Zheludev, Ivan N.
    • Other Affiliation: Stanford University
  • Hagey, Rachel J.
    • Other Affiliation: Stanford School of Medicine
  • Haslecker, Raphael
    • Other Affiliation: Harvard University
  • Hou, Yixuan J.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Kretsch, Rachael
    • Other Affiliation: Stanford University
  • Pintilie, Grigore D.
    • Other Affiliation: Stanford University
  • Rangan, Ramya
    • Other Affiliation: Stanford University
  • Kladwang, Wipapat
    • Other Affiliation: Stanford University
  • Li, Shanshan
    • Other Affiliation: Stanford University
  • Wu, Marie Teng-Pei
    • Other Affiliation: Harvard University
  • Pham, Edward A.
    • Other Affiliation: Stanford School of Medicine
  • Bernardin-Souibgui, Claire
    • Other Affiliation: Stanford School of Medicine
  • Baric, Ralph S.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Sheahan, Timothy P.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • D'Souza, Victoria
    • Other Affiliation: Harvard University
  • Glenn, Jeffrey S.
    • Other Affiliation: Stanford School of Medicine
  • Chiu, Wah
    • Other Affiliation: Stanford University
  • Das, Rhiju
    • Other Affiliation: Stanford University
Abstract
  • Drug discovery campaigns against COVID-19 are beginning to target the SARS-CoV-2 RNA genome. The highly conserved frameshift stimulation element (FSE), required for balanced expression of viral proteins, is a particularly attractive SARS-CoV-2 RNA target. Here we present a 6.9 Å resolution cryo-EM structure of the FSE (88 nucleotides, ~28 kDa), validated through an RNA nanostructure tagging method. The tertiary structure presents a topologically complex fold in which the 5′ end is threaded through a ring formed inside a three-stem pseudoknot. Guided by this structure, we develop antisense oligonucleotides that impair FSE function in frameshifting assays and knock down SARS-CoV-2 virus replication in A549-ACE2 cells at 100 nM concentration.
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  • Article
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  • In Copyright
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  • Nature Structural & Molecular Biology
Page start
  • 1
Page end
  • 8
Language
  • English
ISSN
  • 1545-9985

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