ABSTRACT
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.
Subject(s)
Antiviral Agents/pharmacology , Coronavirus/drug effects , Filoviridae/drug effects , Host-Pathogen Interactions/drug effects , Multiprotein Complexes/metabolism , Orthomyxoviridae/drug effects , Cell Line , Genes, Suppressor , Models, Molecular , Molecular Targeted Therapy , Protein Binding , RNA, Small Interfering/metabolism , RNA, Viral/genetics , RNA, Viral/metabolism , Saccharomyces cerevisiae/genetics , Viral Proteins/metabolism , Virus Replication/drug effectsABSTRACT
Humans are capable of learning many new walking patterns. People have learned to snowshoe up mountains, racewalk marathons, and march in precise synchrony. But what is required to learn a new walking pattern? Here, we demonstrate that people can learn new walking patterns without actually walking. Through a series of experiments, we observe that stepping with only one leg can facilitate learning of an entirely new walking pattern (i.e., split-belt treadmill walking). We find that the nervous system learns from the relative speed difference between the legs-whether or not both legs are moving-and can transfer this learning to novel gaits. We also show that locomotor learning requires active movement: observing another person adapt their gait did not result in significantly faster learning. These findings reveal that people can learn new walking patterns without bilateral gait training, as stepping with one leg can facilitate adaptive learning that transfers to novel gait patterns.