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Cryo-EM and antisense targeting of the 28-kDa frameshift stimulation element from the SARS-CoV-2 RNA genome.
Zhang, Kaiming; Zheludev, Ivan N; Hagey, Rachel J; Haslecker, Raphael; Hou, Yixuan J; Kretsch, Rachael; Pintilie, Grigore D; Rangan, Ramya; Kladwang, Wipapat; Li, Shanshan; Wu, Marie Teng-Pei; Pham, Edward A; Bernardin-Souibgui, Claire; Baric, Ralph S; Sheahan, Timothy P; D'Souza, Victoria; Glenn, Jeffrey S; Chiu, Wah; Das, Rhiju.
  • Zhang K; Departments of Bioengineering, James H. Clark Center, Stanford University, Stanford, CA, USA.
  • Zheludev IN; MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics, Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, China.
  • Hagey RJ; Department of Biochemistry Stanford University, Stanford, CA, USA.
  • Haslecker R; Departments of Medicine (Division of Gastroenterology and Hepatology) and Microbiology & Immunology, Stanford School of Medicine, Stanford, CA, USA.
  • Hou YJ; Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA.
  • Kretsch R; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Pintilie GD; Biophysics Program, Stanford University, Stanford, CA, USA.
  • Rangan R; Departments of Bioengineering, James H. Clark Center, Stanford University, Stanford, CA, USA.
  • Kladwang W; Biophysics Program, Stanford University, Stanford, CA, USA.
  • Li S; Department of Biochemistry Stanford University, Stanford, CA, USA.
  • Wu MT; Departments of Bioengineering, James H. Clark Center, Stanford University, Stanford, CA, USA.
  • Pham EA; MOE Key Laboratory for Membraneless Organelles and Cellular Dynamics, Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, China.
  • Bernardin-Souibgui C; Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA.
  • Baric RS; Departments of Medicine (Division of Gastroenterology and Hepatology) and Microbiology & Immunology, Stanford School of Medicine, Stanford, CA, USA.
  • Sheahan TP; Departments of Medicine (Division of Gastroenterology and Hepatology) and Microbiology & Immunology, Stanford School of Medicine, Stanford, CA, USA.
  • D'Souza V; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Glenn JS; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Chiu W; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Das R; Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA.
Nat Struct Mol Biol ; 28(9): 747-754, 2021 09.
Article in English | MEDLINE | ID: covidwho-1370728
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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Full text: Available Collection: International databases Database: MEDLINE Main subject: RNA, Viral / Frameshift Mutation / Oligonucleotides, Antisense / Cryoelectron Microscopy / Response Elements / SARS-CoV-2 / COVID-19 Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: Nat Struct Mol Biol Journal subject: Molecular Biology Year: 2021 Document Type: Article Affiliation country: S41594-021-00653-y

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Full text: Available Collection: International databases Database: MEDLINE Main subject: RNA, Viral / Frameshift Mutation / Oligonucleotides, Antisense / Cryoelectron Microscopy / Response Elements / SARS-CoV-2 / COVID-19 Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: Nat Struct Mol Biol Journal subject: Molecular Biology Year: 2021 Document Type: Article Affiliation country: S41594-021-00653-y