Picornaviruses are responsible for a variety of human and animal diseases, ranging from hepatitis A, through polio to foot-and-mouth disease and the common cold. We have a track record in the structural analysis of several of these viruses and are now working closely with a number of groups to investigate if it is possible to design a generic approach to the development of improved vaccines by structure led redesign of the virus capsid. Our first target has been foot-and-mouth disease virus and we have now successfully designed a first generation of modified virus capsids with improved properties. We propose to build on this by first fully testing a novel free-energy in silico method for predicting the effect of mutations by proposing a number of further changes. We will then validate these by experimental characterisation of the properties and structure of the modified capsids, roll out the methodology to a number of picornaviruses (eg poliovirus and EV71) and, with our collaborators, test efficacy in animal models. A key part of this work will be the development, in collaboration with the Diamond synchrotron, of improved methods for the analysis of challenging crystals and in situ high resolution structure determination. These methods will also be applied to important picornaviruses of currently unknown structure.
This project is inherently multi-disciplinary in its approach so that training will be provided in a range of methods. These will range from the use of advanced in silico tools through to biochemical and biophysical analyses (using methods such as thermofluor stability analysis and multi angle laser light scattering). There will be the opportunity to perform molecular biology experiments and prepare virus particles and the student would be expected to follow this up with crystallisation, atomic resolution structure determination and analysis.
Protein Science & Structural Biology
Project reference number: 241
| Name | Department | Institution | Country | |
|---|---|---|---|---|
| Prof David Stuart FRS | Structural Biology | Oxford University | UK | stuart-pa@strubi.ox.ac.uk |
There are no publications listed for this DPhil project.