Investigation of the measles entry mechanism to inhibit the process of infection

• Applicant: Dr. Silke Kleinboelting
• Subject Area: Structural Biology ; Biochemistry ; Immunology ; Virology
• Term: from 2017 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 340917223

The relevance of highly pathogenic viruses, especially the measles virus (MeV), which infects roughly 20 million people per year, is increasing for the last few years, although vaccination with live-attenuated virus is possible. At present no effective therapeutics after MeV outbreak are available and vaccination is not possible for infants. A wide range of complications associated with MeV infections like a primary pneumonia or encephalitis and a lethal rate of three out of 1000 in industrialized and up to 25% in developing countries are known.MeV belongs to the paramyxovirus family which consists of enveloped, negative stranded RNA viruses. For infection of the host cells MeV needs two proteins: an attachment protein (H protein), which mediates particle attachment to host cells and a fusion (F protein) glycoprotein. Recent studies highlighting the core mechanism of paramyxovirus entry have great potential to facilitate rational design of antiviral drugs and effective vaccine development, but despite significant recent advances, many key steps of paramyxovirus entry into host cells remain poorly understood. This research proposal describes new approaches to investigate the MeV glycoproteins as a representative for the paramyxovirus entry mechanisms. The results will reveal functional similarities and differences between the viruses of the paramyxovirus family and verifying current models for their entry mechanisms. The research will focus mainly on molecular and structural based methods to visualize the H and F protein and the entry complex of both proteins. Recent improvements in cryo-electron microscopy provide an atomic resolution of protein complexes. The results of this research will provide a better understanding of the viral entry process and enhance our ability to develop novel anti-viral treatments to prevent spreading of the virus. Besides small molecule inhibitors against the F protein also the H-F complex will be considered as a target to block virus entry. For the small molecule screening a cost effective and efficient method will be established to find suitable candidates. Based on an inhibitor complex structure of a known F protein Inhibitor, which will be solved in this project, a virtual screening (docking) will be performed. Details of the complex entry mechanism will provide a chance to develop new specific inhibitors to target the measles virus post infection. The results of this proposed work could lead to new anti-measles virostatic agents to treat an acute infection which is necessary based on the reduced vaccinate population and the comparable high lethal rate by measles viruses.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Theodore Jardetzky