Our specific approach was based on previous success with the use of a modified STAT1 signaling pathway. In this work, we demonstrated that a designer form of STAT1 (designated STAT1-CC based on double-cysteine substitutions) was able to enhance IFN signaling and better control viral replication [13] . Although STAT1-CC gene expression would be challenging to translate to practical application, the mechanism of action served as a guide to design a screening strategy to identify small molecules that could mimic the antiviral benefit. In that regard, we also recognized that phenotypic screening approaches have proven to be more effective than target-based approaches for the discovery of first-in-class small molecule drugs [38] . Thus, target-based approaches (defined as direct drug action on a particular target) allow for analysis and refinement of structure and function but can also waste resources when the molecular hypotheses used to design screening assays may not be relevant to the disease. Meanwhile, phenotypic screening can take longer in terms of hit-to-lead development but provide more proteins in the pathway to be targeted and do not require prior knowledge of molecular mechanisms of action. Most importantly, the activity found in phenotypic-based approaches is often more effectively translated into therapeutic impact in disease models. For the present work, we take advantage of both of these strategies to some extent and devise a screen that incorporates molecular mechanism (i.e., enhancing a specific type of IFN signaling pathway) and the need to achieve phenotype (i.e., identifying any compound that could increase this type of signaling pathway regardless of specific mechanism).