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