Structural and functional conservation of the programmed -1 ribosomal frameshift signal of SARS-CoV-2
| Autor: | Josue San Emeterio, Alexandra N. Olson, Jonathan D. Dinman, Jamie A. Kelly, Sneha Munshi, Michael T. Woodside, Lois Pollack, Krishna Neupane |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0303 health sciences
Messenger RNA viruses Attenuator (genetics) Computational biology Biology 010402 general chemistry medicine.disease_cause 01 natural sciences Small molecule Ribosomal frameshift digestive system diseases 0104 chemical sciences 3. Good health Frameshift mutation 03 medical and health sciences Viral replication medicine Pseudoknot 030304 developmental biology Coronavirus |
| DOI: | 10.1101/2020.03.13.991083 |
| Popis: | 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 over a year to develop a vaccine, the 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 employs a structurally unique three-stemmed mRNA pseudoknot to stimulate high rates of −1 PRF, and 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 and functional analyses revealed that both elements promote similar rates of −1 PRF and that silent coding mutations in the slippery sites and in all three stems of the pseudoknot strongly ablated −1 PRF activity. The upstream attenuator hairpin activity has also been functionally retained. Small-angle x-ray scattering indicated that the pseudoknots in SARS-CoV and SARS-CoV-2 had the same conformation. Finally, a small molecule previously shown to bind the SARS-CoV pseudoknot and inhibit −1 PRF was similarly effective against −1 PRF in SARS-CoV-2, suggesting that such frameshift inhibitors may provide promising lead compounds to counter the current pandemic. |
| Databáze: | OpenAIRE |
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