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Structural and functional conservation of the programmed -1 ribosomal frameshift signal of SARS-CoV-2

Jamie A. Kelly, View ORCID ProfileJonathan D. Dinman
doi: https://doi.org/10.1101/2020.03.13.991083
Jamie A. Kelly
Department of Cell Biology and Molecular Genetics, University of Maryland, College Park MD 20742
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Jonathan D. Dinman
Department of Cell Biology and Molecular Genetics, University of Maryland, College Park MD 20742
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  • ORCID record for Jonathan D. Dinman
  • For correspondence: dinman@umd.edu
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Abstract

17 years after the SARS-CoV epidemic, the world is facing the COVID-19 pandemic. COVID-19 is caused by a coronavirus named SARS-CoV-2. Given the most optimistic projections estimating that it will take more than a year to develop a vaccine, our best short term strategy may lie in identifying virus-specific targets for small molecule interventions. All coronaviruses utilize a molecular mechanism called -1 PRF to control the relative expression of their proteins. Prior analyses of SARS-CoV revealed that it utilizes a structurally unique three-stemmed mRNA pseudoknot to stimulate high rates of -1 PRF, that it also harbors a -1 PRF attenuation element. Altering -1 PRF activity negatively impacts virus replication, suggesting that this molecular mechanism may be therapeutically targeted. Here we present a comparative analysis of the original SARS-CoV and SARS-CoV-2 frameshift signals. Structural analyses reveal that the core -1 PRF signal, composed of the U UUA AAC slippery site and three-stemmed mRNA pseudoknot is highly conserved. In contrast, the upstream attenuator hairpin is less well conserved. Functional assays revealed that both elements promote similar rates of -1 PRF and that silent coding mutations in the slippery site strongly ablate -1 PRF activity. We suggest that molecules that were previously identified as inhibiting SARS-CoV mediated -1 PRF may serve as lead compounds to counter the current pandemic.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted March 15, 2020.
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Structural and functional conservation of the programmed -1 ribosomal frameshift signal of SARS-CoV-2
Jamie A. Kelly, Jonathan D. Dinman
bioRxiv 2020.03.13.991083; doi: https://doi.org/10.1101/2020.03.13.991083
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Structural and functional conservation of the programmed -1 ribosomal frameshift signal of SARS-CoV-2
Jamie A. Kelly, Jonathan D. Dinman
bioRxiv 2020.03.13.991083; doi: https://doi.org/10.1101/2020.03.13.991083

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