About the Project
This project is one of a number that are in competition for funding from the ‘GW4 BioMed MRC Doctoral Training Partnership’ which is offering up to 18 studentships for entry in September/October 2019.
The DTP brings together the Universities of Bath, Bristol, Cardiff and Exeter to develop the next generation of biomedical researchers. Students will have access to the combined research strengths, training expertise and resources of the four research-intensive universities.
SUPERVISORY TEAM:
Lead supervisor: Dr Susan Crennell, Department Biology & Biochemistry (University of Bath)
Co-supervisors: Dr Andrew Watts (University of Bath), Dr Marc van der Kamp (University of Bristol), Professor Jean van den Elsen (University of Bath)
THE PROJECT:
Chagas’ Disease (CD), the cause of 10,000 deaths a year in Latin America, is a WHO ‘Neglected Tropical Disease’, since after an acute phase with non-specific symptoms, there is no effective treatment. CD is caused by Trypanosoma cruzi, infection usually arising from a bite from an infected insect. One of the virulence factors produced by T. cruzi in human hosts is the surface protein trans-sialidase (TcTS) which transfers terminal sugars (sialic acids) from host cells to the trypanosome, helping it to evade the immune system. In the two decades since the determination of the TcTS structure, intensive structure-based drug design programmes have failed to discover effective inhibitors. Recently we have discovered a novel inhibitory site on TcTS, binding amino-phosphonate compounds. The best of these has an IC50 of 15microM, comparable to the best published inhibitors. The discovery of this site opens a significant new line of anti-trypanosome research but poses many questions for instance: what is the inhibition mechanism, does this site have a role in substrate recognition or enzyme function, can targeting this site permit stronger inhibition?
This project seeks to evaluate the potential of this new TcTS allosteric site to provide novel therapeutics against CD. Following analysis of the new TcTS site to design compounds binding more tightly and specifically, these will be synthesised and their effectiveness tested against TcTS in vitro. Initial toxicity testing can be carried out in an invertebrate model (Manduca sexta caterpillars). Leading compounds will be sent to our collaborator in Argentina for in vivo testing in mammalian T. cruzi models. Inhibitor binding will be analysed by crystallography using X-ray data collected in-house and at the Diamond synchrotron. The mechanism of inhibition distant from the catalytic centre is unclear so computational analysis of the structure in the presence and absence of inhibitor using molecular dynamics will suggest hypotheses that can be tested through mutagenesis. An understanding of mechanism will inform the design of better inhibitors.
Through this research project the student will gain experience in a wide range of techniques across different disciplines and Universities, including protein production, enzyme characterisation, X-ray crystallography and toxicity (M.sexta) studies (Bath Biology & Biochemistry), inhibitor design, synthesis and evaluation (Bath Pharmacy & Pharmacology) and computational analysis, particularly molecular dynamics simulation (Bristol). Results will be communicated in research publications, and at conferences. Outcomes from the project will have immediate impact on the many academic and commercial groups working on CD therapies. Strong IP protection for allosteric regulation of TcTS will be necessary and we intend to file composition of matter patent applications on any lead compounds once structure-activity relationships have been established.
APPLICATIONS:
Applicants for a studentship must have obtained, or be about to obtain, a First or Upper Second Class UK Honours degree, or the equivalent qualifications gained outside the UK, in an area appropriate to the skills requirements of the project.
IMPORTANT: In order to apply for this project, you should apply using the DTP’s online application form: https://cardiff.onlinesurveys.ac.uk/gw4-biomed-mrc-dtp-student-2019
More information on the application process may be found here:
http://www.gw4biomed.ac.uk/doctoral-students/
You do NOT need to apply to the University of Bath at this stage – only those applicants who are successful in obtaining an offer of funding form the DTP will be required to submit an application to study at Bath.
Funding Notes
A full studentships will cover UK/EU tuition fees, a training support fee and a stipend (£14,777 p.a. for 2018/19, updated each year) for 3.5 years.
UK and EU applicants who have been residing in the UK since September 2016 will be eligible for a full award; a limited number of studentships may be available to EU applicants not meeting the residency requirement. Applicants who are classed as Overseas for tuition fee purposes are not eligible for funding. More information on eligibility may be found on the DTP’s website: http://www.gw4biomed.ac.uk/eligibility/
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