Technologies applied for host-directed drug discovery include cDNA and siRNA-based microarray analyses combined with pathway-guided data mining [47, 48, 49, 50, 51] , loss-of-function screens using aptamers or small oligonucleotides [52, 53, 54, 55, 56, 57, 58] , protein array analyses [59] and chemical library screening [60, 61] . By combining automated library screening [19] with counter screens against a variety of related viral pathogens of the myxovirus families, we have identified a candidate scaffold that, after moderate hit-to-lead chemistry, adheres to the profile of a host-directed antiviral based on several lines of evidence: I) antiviral activity is host cell species-dependent, indicating specific interaction with a distinct host factor rather than a viral component. Host cell-specific activity is incompatible with compound docking to conserved viral factors. For example, carbohydrate structures exposed on viral envelope glycoproteins that are targeted by antiviral lectins such as pradimicin A [62] . Furthermore, it is incompatible with an undesirable unspecific, promiscuous mode of action of the compound [63] ; II) affinities against a panel of human pathogens of the paramyxovirus family as well as laboratory adapted and wild type influenza virus isolates were very similar throughout (average EC 50 concentrations are ,40 nM). Equivalent active concentrations argue against compound docking to distinct viral components and suggest that inhibition of distinct myxovirus families follows the same mechanism of action; III) in vitro adaptation attempts to induce viral resistance were unsuccessful even after extended exposure times to the drug. A full assessment of the frequency of viral escape from inhibition by JMN3-003 will certainly need to include in vivo virus adaptation attempts in suitable animal models, since the rate of resistance build-up may vary between tissue culture and in vivo settings. We nevertheless reliably induced resistance in less than 30 days to a pathogen-directed MeV RdRp inhibitor that was analyzed in parallel, which is fully consistent with our previous experience [36] and provides confidence for the validity of our overall experimental design for viral adaptation.