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Targeting a novel allosteric site on Trypanosoma cruzi trans-sialidase for future Chagas' disease therapy

University of Bath - Department of Biology and Biochemistry

Qualification Type: PhD
Location: Bath
Funding for: UK Students, EU Students
Funding amount: £14,777 stipend, Home tuition fees, and Training Support Fee
Hours: Full Time
Placed On: 8th October 2018
Closes: 23rd November 2018

Supervisory team:

Dr Susan Crennell (University of Bath), Dr Andrew Watts (Bath), Dr Marc van der Kamp (Bristol), Professor Jean van den Elsen (Bath)

Email contact:

bsssjc@bath.ac.uk

Overview

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.

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 active site 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 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 studies, inhibitor design, synthesis and evaluation, and computational analysis, particularly molecular dynamics simulation . Results will be communicated in research publications, and at conferences.

IMPORTANT: You should apply using the DTP’s online application form:  https://cardiff.onlinesurveys.ac.uk/gw4-biomed-mrc-dtp-student-2019

For more information on the application process visit:

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 from the DTP will be required to submit an application to study at Bath.

Funding

Studentships cover Home tuition fees, Training Support Fee and stipend (£14,777 p/a, 2018/9 rate) and are open to UK/EU applicants who have been resident in the UK since September 2016.

Start date

30 September 2019

Relevant subject areas

  • Biochemistry
  • Immunology
  • Microbiology
  • Parasitology
  • Pharmacology / Toxicology
  • Structural Biology
  • Biochemistry
  • Computational Chemistry
   
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