Agents that modulate an interaction of an FBL2 protein with an NS5A or NS5B Flaviviridae protein in a mixture are identified by contacting the mixture with a candidate agent under conditions wherein but for the presence of the agent, the FBL2 protein and the Flaviviridae protein engage in a reference interaction; and detecting an agent-biased interaction. Flaviviridae replication is inhibited by contacting a Flaviviridae-infected cell with an FBL2-specific reagent; and detecting a resultant Flaviviridae replication inhibition.