HPEV3 STRUCTURE · HPeV3 structural and functional studies

HPeV3 structural and functional studies

One step forward in developing drugs against sepsis-causing virus in newborns Resolving the high-resolution structure of a parechovirus by Prof Sarah Butcher’s group at the University of Helsinki helps the development of antiviral drugs. Small RNA viruses with single stranded RNA genome, picornaviruses, is a large virus group that comprise many human pathogens causing wide range of disease symptoms. Human parechovirus type 3 is a picornavirus that can cause severe infections resulting in sepsis and central nervous system disease in newborns. So far the most promising anti-picornaviral drug candidates do not have any effect on the parechovirus, therefore new effective means have to be found. Marie Curie Postdoctoral Research Fellow at the University of Helsinki, Dr Ausra Domanska studied the structural and functional aspects of the human parechovirus type 3. In close collaboration with her colleague Dr Shabih Shakeel, they determined structures of the virus alone and in complex with the antibody fragments recognising this virus. The three-dimensional models were created by collecting thousands of images of virus with an electron microscope under -190 °C (method called cryo-electron microscopy). The images were then computationally analysed and combined. High resolution three-dimensional models (atomic models) help researchers to see atomic details of the virus that are important for new drug design and development. This project revealed unique features of parechoviruses that have not been seen in other picornaviruses. About a quarter of the genome is in close contact with the capsid proteins (shell of the virus particle), leading to highly ordered RNA. The atomic model of the virus shows a distinct way how viral proteins interact with each other to stabilize the capsid. The best studied anti-picornaviral drug pleconaril and its derivatives work well against enteroviruses, a large group of picornaviruses. We could see from the structure, that In parechovirus type 3 the pleconaril binding site is blocked and therefore the drug does not work against this virus group. Monoclonal human antibodies were generated by Dr Tim Beaumont (AIMM Therapeutics) and Dr Katja Wolthers at Amsterdam Medical Centre (the Netherlands) that specifically bind to parechovirus type 3, but do not significantly block the viral infection. We determined the structure of the virus and antibody together. We could then map where the antibody binds to the surface of the virus and worked out which were the key atoms making the interaction possible. Furthermore, Dr Domanska plans to ‘improve’ the monoclonal antibody by modifying these interactions so that antibody becomes more effective at stopping the virus infection. In the absence of antiviral drugs, developing broadly neutralising monoclonal antibodies as therapeutic antibodies against parechovirus type 3 is one of the most promising treatment options for clinicians in the near future. _________ Shakeel, S. et al. Multiple capsid-stabilizing interactions revealed in a high-resolution structure of an emerging picornavirus causing neonatal sepsis. Nat. Commun. 7:11387 doi: 10.1038/ncomms11387 (2016) http://www.nature.com/articles/ncomms11387 Contact details: Ausra Domanska, PhD Institute of Biotechnology and Department of Biological Sciences Viikinkaari 1, 00014 University of Helsinki, Finland website http://blogs.helsinki.fi/butcher/ Attached document: Monoclonal antibody fragments (orange) bound to human parechovirus 3 (blue); picture by Ausra Domanska

Data: CORDIS, © European Union