Abstract
The coronavirus causing the COVID-19 pandemic, SARS-CoV-2, uses −1 programmed ribosomal frameshifting (−1 PRF) to control the relative expression of viral proteins. As modulating −1 PRF can inhibit viral replication, the RNA pseudoknot stimulating −1 PRF may be a fruitful target for therapeutics treating COVID-19. We modeled the unusual 3-stem structure of the stimulatory pseudoknot of SARS-CoV-2 computationally, using multiple blind structural prediction tools followed by μs-long molecular dynamics simulations. The results were compared for consistency with nuclease-protection assays and single-molecule force spectroscopy measurements of the SARS-CoV-1 pseudoknot, to determine the most likely conformations. We found several possible conformations for the SARS-CoV-2 pseudoknot, all having an extended stem 3 but with different packing of stems 1 and 2. Several conformations featured rarely-seen threading of a single strand through junctions formed between two helices. These structural models may help interpret future experiments and support efforts to discover ligands inhibiting −1 PRF in SARS-CoV-2.
Highlights
The COVID-19 pandemic caused by the novel Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) has spread across the globe since the virus emerged in late 2019 [1]
The coronavirus that causes COVID-19 controls the production of key viral proteins through a process known as programmed ribosomal frameshifting
Inhibiting −1 PRF was found to suppress replication of the close relative SARS-CoV-1 by orders of magnitude [9,10], suggesting that the same strategy may be effective against SARS-CoV-2
Summary
The COVID-19 pandemic caused by the novel Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) has spread across the globe since the virus emerged in late 2019 [1]. Given the high infectivity of SARS-CoV-2 and the novel immunological challenge it poses to human hosts, epidemiological modeling suggests that recurring outbreaks with elevated mortality can be expected even despite successful public-health responses, until vaccines or preventive drugs can be found to inhibit transmission [2]. The discovery of effective treatment therapeutics is one of the central goals of research into COVID-19 [3]. Like other human coronaviruses [5], SARS-CoV-2 depends on −1 programmed ribosomal frameshifting (−1 PRF) to produce essential proteins at regulated levels [6]. Inhibiting −1 PRF was found to suppress replication of the close relative SARS-CoV-1 by orders of magnitude [9,10], suggesting that the same strategy may be effective against SARS-CoV-2
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