The broad long-term objectives of the proposed work are to develop effective medical countermeasures to be used for the treatment of viral infectious disease caused by exposure to human coronaviruses. The work will focus on the discovery and development of peptide-based therapeutics for the treatment of persons infected with the newly identified Middle Eastern Respiratory Syndrome coronavirus (MERS CoV) with potentially wider utility of these therapeutics for use in the treatment of infections caused by the broad family of human coronaviruses. Our preliminary data indicate that short peptides which are derived from sequences representing novel functional domains within the loop region of the Spike protein of the SARS coronavirus are potent inhibitors of both SARS and MERS infection in vitro. We propose to design peptide drug candidates for the treatment of MERS CoV infection by using a combined approach of empiric antiviral screening together with computational methods as a means to identify peptides that interact with lipid bilayer membranes. Research in our laboratories indicates that these peptides exert potent antiviral activity by inhibiting fusion of he viral envelop to the host cell membrane. The specific aims of the proposed work are three-fold and include: 1.) Using well-established methods to evaluate the in vitro efficacy of peptides against all members of the broad family of human coronaviruses; 2.) Enhancing the safety, throughput and reproducibility of our antiviral screening methods by developing a pseudoparticle system for human coronaviruses; 3.) Development and validation of the mink as an in vivo model for evaluating the pathophysiology of MERS CoV infection and for testing the in vivo efficacy of lead peptides discovered in our screening program for activity against a valid model of MERS CoV infection. Successful completion of the specific aims will establish a robust discovery platform for the rapid identification of novel antiviral agents against emerging pathogens. The development of an animal model will be an essential step in order to support the introduction of these compounds into clinical testing as potential human therapeutics.