The rabies virus (RABV) phosphoprotein (P) has a central role in the neutralization of host innate immune defences by acting to antagonize type I interferon (IFN) signalling, thereby preventing induction of IFN-stimulated genes (ISGs) in target cells. Specifically, P-protein inhibits IFN-α and IFN-γ-mediated transcriptional responses by interacting directly with the signal transducer and activator of transcription 1 (STAT1) to prevent its activation and establishment of an antiviral state in infected cells. This interaction was recently demonstrated to be critical to disease in animals, with inhibition of the interaction rendering an otherwise 100% lethal RABV strain non-lethal in mice. Thus, the interaction represents a clear target for therapies. While the P-protein C-terminal domain (CTD) is known to interact with STAT1, the molecular details of this interaction remain largely unresolved. We are using protein structure analysis by NMR to determine the residues/sites that mediate interaction of the CTD with STAT1, and thereby gain insight into the mechanism by which P-protein inhibits IFN/STAT1 responses. We have expressed and purified the CTD and STAT1 at high yields and so have demonstrated a clear interaction using fluorescence-labelled analytical ultracentrifugation (AUC). We have used cross-saturation transfer on 2 H, 15 N CTD and unlabelled STAT1 to identify key interacting residues on the CTD. We will present novel insights from these studies concerning the extent and composition of the molecular interface, which represent the first direct structural data for a viral IFN-antagonist- STAT1 interaction as well as our approaches to design broad-spectrum antiviral drugs targeting this interface.