With 16 annual registered deaths in Europe at the last count by the European Centre for Disease Prevention and Control (ECDC), tick-borne encephalitis virus (TBEV) is not currently high on the public agenda. But the virus transmitted by ticks to mammals, including humans, is on the rise in many parts of Europe and Asia, says Maria Anastasina, researcher at the University of Helsinki. That could be due to climate change expanding the seasons and habitats suitable for ticks or to increased human recreational use of hotspot areas. Not only is TBEV life-threatening, it causes inflammation of the brain tissues that can result in lasting neurological damage, as the ECDC explains. With the support of the Marie Skłodowska-Curie Actions, Anastasina has laid the foundations for future treatments for the virus, which has spread steadily in Europe, showing a record three-fold increase in southern Germany this year, says the ECDC. During the 2STOP_TBE project, the researcher built three-dimensional models of TBEV to learn more about the structure of the virus and to study molecular details of how it functions, discovering possible ways to suppress the virus using small molecules. “Our data will be used for drug screening and the optimisation of candidate drugs,” says Anastasina, who was supervised by Sarah Butcher, professor and director of FINStruct’s Cryogenic Electron Microscopy Facility. “We will soon provide details about the binding of candidate drugs to the virus, which will be valuable to improve their efficacy.” The researchers shared their knowledge about TBEV in ‘Tick-Borne Encephalitis Virus: A Structural View’, MDPI.
Paving the way for pharmaceuticals
Determining the structure of the virus at different stages of its life cycle was challenging, but it is key for drug discovery. The researchers resolved the problem by developing protocols to obtain highly purified, concentrated preparations of different TBEV particles. They determined structures of these particles using cryogenic electron microscopy, a cutting-edge technology that allowed researchers to view and analyse the macromolecules in their natural, hydrated state, undamaged by chemical fixatives. One promising target for pharmaceuticals is the recently discovered pocket on the surface of a virus of the same family. “There are candidate drugs for TBEV that bind to a similar pocket in this virus,” explains Anastasina. “As we built a high-resolution model of TBEV where this target area can be seen well, we will now use this knowledge to investigate how exactly the proposed drugs bind to this pocket and what chemical improvements are needed to turn these drug candidates into TBEV antivirals.” Seeking additional antiviral targets, the researchers also investigated the maturation of the TBEV particle, identified cellular proteins that are required by the virus and established a platform for drug screening, which they will now use to find inhibitors of viral genome synthesis. The progress the project made on TBEV could prove vital since people are often unaware that they are living in or visiting a tick-infested area, where the virus is present. “It is very difficult to say how common the virus is,” concludes Anastasina.
2STOP_TBE, tick-borne encephalitis, cryogenic electron microscopy, virus