Marie Teng-Pei Wu

Harvard University

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Edward A. Pham

University of Massachusetts Amherst

Rachel J. Hagey

Stanford Medicine

Raphael Haslecker

Harvard University

Ralph S. Baric

University of North Carolina at Chapel Hill

Timothy P. Sheahan

University of North Carolina at Chapel Hill

Grigore Pintilie

Stanford University

Wipapat Kladwang

Stanford University

Ivan N. Zheludev

Stanford University

Rachael C. Kretsch

Stanford University

Ramya Rangan

Stanford University

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Stanford University

Stanford Medicine

Harvard University

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Howard Hughes Medical Institute

University of North Carolina at Chapel Hill

Stratford University

University of Science and Technology of China

Anhui Provincial Center for Disease Control and Prevention

Capital Medical University

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

Carolina Digital Repository (University of North Carolina at Chapel Hill) (2021)

Kaiming Zhang Ivan N. Zheludev Rachel J. Hagey Raphael Haslecker Yixuan J. Hou

DNA Transposable Elements

10.17615/q6mz-jr12

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Genetic Recoding in HIV-1 and IBV Is Modulated by Alternate RNA Structures

Marie Teng-Pei Wu

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The 28-kDa Frameshift Stimulation Element from the SARS-CoV-2 RNA Genome

Kai Zhang Ivan N. Zheludev Rachel J. Hagey Marie Teng-Pei Wu Raphael Haslecker

DNA Transposable Elements

10.2210/pdb6xrz/pdb

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Alternate RNA Structures

Cold Spring Harbor Perspectives in Biology (2020)

Marie Teng-Pei Wu Victoria D’Souza

Marie Teng-Pei Wu and Victoria D'Souza Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138 Correspondence: dsouza{at}mcb.harvard.edu

Nucleic acid structure

Energy landscape

10.1101/cshperspect.a032425

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Cryo-electron Microscopy and Exploratory Antisense Targeting of the 28-kDa Frameshift Stimulation Element from the SARS-CoV-2 RNA Genome

bioRxiv (Cold Spring Harbor Laboratory) (2020)

Kaiming Zhang Ivan N. Zheludev Rachel J. Hagey Marie Teng-Pei Wu Raphael Haslecker

Abstract Drug discovery campaigns against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) are beginning to target the viral RNA genome 1, 2 . The frameshift stimulation element (FSE) of the SARS-CoV-2 genome is required for balanced expression of essential viral proteins and is highly conserved, making it a potential candidate for antiviral targeting by small molecules and oligonucleotides 3–6 . To aid global efforts focusing on SARS-CoV-2 frameshifting, we report exploratory results from frameshifting and cellular replication experiments with locked nucleic acid (LNA) antisense oligonucleotides (ASOs), which support the FSE as a therapeutic target but highlight difficulties in achieving strong inactivation. To understand current limitations, we applied cryogenic electron microscopy (cryo-EM) and the Ribosolve 7 pipeline to determine a three-dimensional structure of the SARS-CoV-2 FSE, validated through an RNA nanostructure tagging method. This is the smallest macromolecule (88 nt; 28 kDa) resolved by single-particle cryo-EM at subnanometer resolution to date. The tertiary structure model, defined to an estimated accuracy of 5.9 Å, presents a topologically complex fold in which the 5′ end threads through a ring formed inside a three-stem pseudoknot. Our results suggest an updated model for SARS-CoV-2 frameshifting as well as binding sites that may be targeted by next generation ASOs and small molecules.

Pseudoknot

Translational frameshift

Coronavirus

10.1101/2020.07.18.209270

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

Nature Structural & Molecular Biology (2021)

Kaiming Zhang Ivan N. Zheludev Rachel J. Hagey Raphael Haslecker Yixuan J. Hou

DNA Transposable Elements

10.1038/s41594-021-00653-y

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Citations (138)