It has been suggested for different viral pathogens that a hostdirected antiviral approach has the potential to reduce the frequency of viral escape from inhibition compared to direct targeting of pathogen components [14, 15] . To explore whether resistance to JMN3-003 could be induced experimentally, we attempted stepwise viral adaptation to growth in the presence of the compound in comparison with the pathogen-specific MeV RdRp inhibitor AS-136A [36] . Following an escalating dose scheme, inhibitor concentrations were doubled when virusinduced cytopathicity became detectable microscopically. While robust resistance to the pathogen-targeted AS-136A control emerged rapidly in an approximate 15 to 20-day time window (tolerated dose at the end of adaptation was $30 mM, equivalent to $100-fold resistance), only marginal increases in the tolerated dose could be detected for JMN3-003 after 90 days of continued viral incubation in the presence of the substance (figure 8). These results are consistent with a host-directed mechanism of action of JMN3-003 and suggest the existence of a systemic barrier that prevents rapid viral escape from inhibition by the article.