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Anti-Frameshifting Ligand Active against SARS Coronavirus-2 Is Resistant to Natural Mutations of the Frameshift-Stimulatory Pseudoknot.
Neupane, Krishna; Munshi, Sneha; Zhao, Meng; Ritchie, Dustin B; Ileperuma, Sandaru M; Woodside, Michael T.
  • Neupane K; Department of Physics, University of Alberta, Edmonton, AB T6G 2E1, Canada.
  • Munshi S; Department of Physics, University of Alberta, Edmonton, AB T6G 2E1, Canada.
  • Zhao M; Department of Physics, University of Alberta, Edmonton, AB T6G 2E1, Canada.
  • Ritchie DB; Department of Physics, University of Alberta, Edmonton, AB T6G 2E1, Canada.
  • Ileperuma SM; Department of Physics, University of Alberta, Edmonton, AB T6G 2E1, Canada.
  • Woodside MT; Department of Physics, University of Alberta, Edmonton, AB T6G 2E1, Canada. Electronic address: michael.woodside@ualberta.ca.
J Mol Biol ; 432(21): 5843-5847, 2020 10 02.
Article in English | MEDLINE | ID: covidwho-753245
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ABSTRACT
SARS-CoV-2 uses -1 programmed ribosomal frameshifting (-1 PRF) to control expression of key viral proteins. Because modulating -1 PRF can attenuate the virus, ligands binding to the RNA pseudoknot that stimulates -1 PRF may have therapeutic potential. Mutations in the pseudoknot have occurred during the pandemic, but how they affect -1 PRF efficiency and ligand activity is unknown. Studying a panel of six mutations in key regions of the pseudoknot, we found that most did not change -1 PRF levels, even when base-pairing was disrupted, but one led to a striking 3-fold decrease, suggesting SARS-CoV-2 may be less sensitive to -1 PRF modulation than expected. Examining the effects of a small-molecule -1 PRF inhibitor active against SARS-CoV-2, it had a similar effect on all mutants tested, regardless of basal -1 PRF efficiency, indicating that anti-frameshifting activity can be resistant to natural pseudoknot mutations. These results have important implications for therapeutic strategies targeting SARS-CoV-2 through modulation of -1 PRF.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Pneumonia, Viral / Gene Expression Regulation, Viral / Coronavirus Infections / Frameshifting, Ribosomal / Small Molecule Libraries / Betacoronavirus Limits: Humans Language: English Journal: J Mol Biol Year: 2020 Document Type: Article Affiliation country: J.jmb.2020.09.006

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Pneumonia, Viral / Gene Expression Regulation, Viral / Coronavirus Infections / Frameshifting, Ribosomal / Small Molecule Libraries / Betacoronavirus Limits: Humans Language: English Journal: J Mol Biol Year: 2020 Document Type: Article Affiliation country: J.jmb.2020.09.006