Infection diseases caused by high pathogenic viruses are some of the major threats to public health and economic development. In recent years, numbers of high pathogenic viruses have led to worldwide pandemics and caused severe infection diseases. Infections with these viruses often are associated with deadly hemorrhagic fevers with extremely high mortality rates, and currently there is no effective therapeutics or vaccines for any of these agents. Some of them are classified as Biosafety Level 4 (BSL-4) pathogens, and also represent potential bioterrorism threats. Therefore, the demand for the understanding of these high pathogenic viruses and inhibition mechanisms to their infection is emerging. The applicant (Dr. Zihe Rao, MCAS, Tsinghua University) and the co-applicant (Dr. David Stuart, FRS, University of Oxford) are both interested in the structure and function of the key protein complexes which are essential for high pathogenic viruses’ infection and replication. In the past several years, both have published a series of high impact works on the structures of hand-foot-and-mouth disease virus (HFMDV), hepatitis A virus (HAV) and other high pathogenic viruses, through X-ray crystallography, EM and other integrated methods. According to our common interests and expertise, we plan to further investigate the structure and function of the protein complexes encoded by high pathogenic viruses, including Ebola/Marburg viruses, HFMDV, SARS-CoV/MERS-CoV, HAV, etc. We will also discover leading compounds to inhibit the infection and replication of high pathogenic viruses based on the structural information.