In toto, we have identified a novel chemical class of viral inhibitors that block viral RdRp activity with a host factormediated profile. A complete activity workup after synthetic identification of a clinical lead analog will be required to fully appreciate the range of the different viral families inhibited by the substance. However, we consider human pathogens of the myxovirus families that are primarily associated with acute disease among the most suitable for host-directed antiviral efforts due to anticipated short treatment regimens. While we cannot exclude that resistance to JMN3-003 may eventually emerge in in vivo settings, our in vitro adaptation efforts support the hypothesis that the mechanism of action of this compound class establishes a strong barrier against rapid viral escape from inhibition.