Viral RNA structures are known to regulate replication but are under-explored as drug targets. In work funded by the Research Corporation for Science Advancement (RCSA), a team led by Professor Amanda Hargrove and Professor Kathryn Mouzakis (LMU) will work to identify the first antivirals that target a SARS-CoV-2 RNA structure critical to effective translation of viral proteins, ultimately inhibiting viral replication.
During an early step in the SARS-CoV-2 lifecycle, the genomic RNA is translated to produce viral proteins critical to the replication cycle. A subset of these proteins, including the RNA-dependent-RNA polymerase (RdRp) targeted by Remdesivir, are made by way of a programmed -1 ribosomal frameshift (-1 PRF). This translational event occurs at the frameshift site (FSS), which includes a highly-conserved RNA pseudoknot structure. Previous work on the related SARS coronavirus revealed that reduction of -1 PRF efficiency drastically reduced viral replication, suggesting that this step in the coronavirus viral life cycle is a viable target. In this work, the team proposes to identify the first SARS-CoV-2 antivirals that target the SARS-CoV-2 FSS pseudoknot structure, decreasing the translation of critical viral proteins like RdRp and inhibiting viral replication. The drug-like antivirals discovered here will be used to determine the tolerability of SARS-CoV-2 viral replication to changes in frameshift efficiency and establish SARS-CoV2 RNA structures as viable drug targets. Given the high conservation of the SARS-CoV-2 FSS pseudoknot and other regulatory RNA structures, we anticipate that RNA-targeted antivirals could be used, likely in combination with other drugs, to impact both current and future coronavirus-associated pandemics.