Project Summary/Abstract The current epidemics of SARS CoV2 is an acute reminder that infectious diseases remain an enormous threat to the well-being and prosperity of human populations, and respiratory viral infections are the leading cause of burden of disease world-wide. Indeed, given their airborne mode of transmission, respiratory viruses are prone to rapid and often initially unrecognized spread with potential for pandemics resulting in significant health, societal, and economic impact. Despite medical progress and vaccination, many infectious diseases have emerged or re-emerged in the second half of the twentieth century. Recent events of viral zoonoses such as the influenza A virus 2009 pandemic, the Middle East Respiratory Syndrome (MERS) coronavirus outbreak, and of course the ongoing CoVID19 pandemic dramatically emphasize the need to expand basic research on such pathogens in order to develop new antiviral therapies with low potential for therapeutic escape. Despite constant efforts of diversification of classes of inhibitors, recurrent emergence of viral resistance towards existing conventional antiviral drugs emphasizes the need for alternative targets less amenable to therapeutic escape, especially non-viral targets such as host cellular factors that promote virus multiplication. Viruses depend on their ability to hijack and control the cellular machinery to multiply and spread through organisms and populations. Hence, compounds inhibiting the virus’s ability to interact with, and rewire, the host cellular machinery are the most promising candidates for host-directed anti-viral therapeutics. Here we propose the development of a systematic strategy to identify inhibitors of viral-host protein-protein interactions. Applying it to influenza A viruses, we will pioneer our discovery pipeline using virus-host PPI involved in the trafficking of viral components or in viral escape of host cell restriction, processes that are strongly dependent on the interactions that the viral proteins engage with host factors. Chemical compounds disrupting biologically- validated PPIs will be screened using a multi-parameter toolkit of assays. The anti-viral potential of validated PPI-inhibiting compounds will be determined using influenza A virus strains of