Author: Neupane, Krishna; Munshi, Sneha; Zhao, Meng; Ritchie, Dustin B.; Ileperuma, Sandaru M.; Woodside, Michael T.
Title: Anti-Frameshifting Ligand Active against SARS Coronavirus-2 Is Resistant to Natural Mutations of the Frameshift-Stimulatory Pseudoknot Cord-id: 8u1sk5si Document date: 2020_9_11
ID: 8u1sk5si
Snippet: 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 6 mutations in key regions of the pseudoknot, we found that most did not change
Document: 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 6 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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