The SKI complex is a broad-spectrum, host-directed antiviral drug target for coronaviruses, influenza, and filoviruses

Significance The SARS-CoV-2 pandemic of 2020 has highlighted the great need for antiviral therapeutics. In this work, we identify a host factor, the SKI complex, is involved in replication of influenza and coronaviruses. Using computational modeling we were able to identify chemicals that interact with the host factor that display broad-spectrum antiviral activity against influenza, coronaviruses, and filoviruses, all of which cause significant morbidity and mortality. Broad-spectrum antiviral therapeutics are sorely needed to combat known and unknown viral pathogens and the work presented here is our first step to developing antivirals to target the SKI complex. The SARS-CoV-2 pandemic has made it clear that we have a desperate need for antivirals. We present work that the mammalian SKI complex is a broad-spectrum, host-directed, antiviral drug target. Yeast suppressor screening was utilized to find a functional genetic interaction between proteins from influenza A virus (IAV) and Middle East respiratory syndrome coronavirus (MERS-CoV) with eukaryotic proteins that may be potential host factors involved in replication. This screening identified the SKI complex as a potential host factor for both viruses. In mammalian systems siRNA-mediated knockdown of SKI genes inhibited replication of IAV and MERS-CoV. In silico modeling and database screening identified a binding pocket on the SKI complex and compounds predicted to bind. Experimental assays of those compounds identified three chemical structures that were antiviral against IAV and MERS-CoV along with the filoviruses Ebola and Marburg and two further coronaviruses, SARS-CoV and SARS-CoV-2. The mechanism of antiviral activity is through inhibition of viral RNA production. This work defines the mammalian SKI complex as a broad-spectrum antiviral drug target and identifies lead compounds for further development.