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Covalent Inhibition of Essential Deubiquitinases of Leishmania

   Department of Chemistry

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  Prof A J Wilkinson, Prof J Mottram  No more applications being accepted  Funded PhD Project (Students Worldwide)

About the Project

The clinical symptoms of Leishmaniasis range from the disfiguring skin lesions of cutaneous leishmaniasis, to the often fatal visceral leishmaniasis. With millions of people at risk in the poorest countries of the world, and the available treatments suffering from serious drawbacks, new therapies are needed. Components of post-translational modification systems have been successfully targeted in the treatment of many human diseases and here we are exploring the ubiquitination system of the parasitic protozoan Leishmania which causes leishmaniasis.

The ubiquitin proteasome system is the primary mechanism for protein degradation in eukaryotic cells. Ubiquitin is attached to target proteins in sequential steps involving E1, E2 and E3 conjugating enzymes. Ubiquitin homeostasis is regulated by the action of deubiquitinases (DUBs), which cleave ubiquitin from ubiquitinated proteins, as well as via processing of ubiquitin precursors. We have shown using genome editing that four DUBs are essential for life cycle transitions of Leishmania parasites, which differentiate from free-living promastigotes in the sandfly to obligate intracellular amastigotes in the mammalian host. The next step is to elucidate the critical cellular processes in which these four DUBs participate. An effective way to approach this is to develop and deploy selective DUB inhibitors. With this in mind, we plan to use GSK’s specialist expertise and knowledge in chemical biology and their application to the identification and development of DUB inhibitors.

In this project, we therefore plan to (i) screen a library of covalent fragments against the four essential DUBs of L. mexicana using mass spectrometry and activity assays, (ii) crystallise DUB:fragment complexes to guide the development of higher potency inhibitors, (iii) develop a method to measure on-target engagement in parasites using an LC-MSMS based quantitative assay and (iv) use inhibitors as chemical tools to probe the downstream biological impact of DUB inhibition and identify substrate proteins and interactors. The project is interdisciplinary combining Chemical Biology, Structural Biology and Parasitology. A key component of this industrial CASE studentship, will be a close collaboration with GSK including a placement at the company providing an opportunity to access their expertise, facilities and collections of compounds.

The WR DTP and the University of York are committed to recruiting future scientists regardless of age, ethnicity, gender, gender identity, disability, sexual orientation or career pathway to date. We understand that commitment and excellence can be shown in many ways and we have built our recruitment process to reflect this. We welcome applicants from all backgrounds, particularly those underrepresented in science, who have curiosity, creativity and a drive to learn new skills.

Entry Requirements: Students with, or expecting to gain, at least an upper second class honours degree, or equivalent, are invited to apply. The interdisciplinary nature of this programme means that we welcome applications from students with backgrounds in any biological, chemical, and/or physical science, or students with mathematical backgrounds who are interested in using their skills in addressing biological questions. 

Programme: PhD in Biological Chemistry (4 years)

Start Date: 1st October 2022 (the student will be affiliated with the Department of Chemistry)

Shortlisted candidates will be interviewed in early March 2022.

Funding Notes

This project is part of the BBSRC White Rose Doctoral Training Partnership in Mechanistic Biology. Appointed candidates will be fully-funded for 4 years. The funding includes:
Tax-free annual UKRI stipend (£15,609 for 2021/22) + £3,000 pa from GSK
UK tuition fees (£4,500 for 2021/22)
Research support and training charges
Placement funding from the industrial partner
We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries to outstanding international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

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