Discovery of small molecules targeting SARS-CoV-2 frameshifting using a rapid yeast platform

The recent outbreak of coronavirus SARS-CoV-2 (2019-2020) leading to the COVID-19 pandemic worldwide has led to increased urgency in identifying strategies to mitigate the spread of coronavirus infection and treat infected individuals. No established drug/vaccine treatments exist, thus there is a need to identify antiviral targets. As evidenced of recurring SARS-CoV (2003) and MERS-CoV (2012) outbreaks, there is also a need for long-term preparations to counteract future emerging coronavirus outbreaks. Identifying and targeting essential mechanisms that are unique to SARS/MERS-CoVs are key to identifying new antiviral compounds and it is likely a combinatorial approach that targets specific steps of SARS-CoV-2 will be needed (similar to antiviral cocktails for HIV and HCV). The goal of this proposal is to rapidly identify novel drugs targeting a unique mechanism in SARS-CoV-2, called -1 frameshifting. The approach will use a rapid yeast platform which has been used successfully to identify drugs that target autophagy, cell-cycle and influenza. Our entire pipeline will identify non-toxic, bioactive compounds that enhance or inhibit -1 frameshifting that will be tested for efficacy in blocking SARS-CoV-2 infection. The identification of small molecules that inhibit or enhance SARS-CoV-2 FS activity will contribute to candidate therapeutic approaches to treat COVID-19 disease and potentially future emerging outbreaks.