University of Dundee

MRC DTP 4 Year PhD Programme: Strategy to identify novel and exploitable anti-malarial drug targets

This project is offered as part of the University of Dundee 4-year MRC DTP Programme “Quantitative and Interdisciplinary approaches to biomedical science”. This PhD programme brings together leading experts from the School of Life Sciences (SLS), the School of Medicine (SoM) and the School of Science and Engineering (SSE) to train the next generation of scientists at the forefront of international science.  The outstanding biomedical research at the University of Dundee was recognised by its very high rankings in REF 2014, with Dundee rated as the top University for Biological Sciences in the UK.  A wide range of projects are available within this programme crossing exceptional strengths in four key areas: Infection and Disease; Responses to Cellular Stresses; Development, Stem Cells and Neurobiology; and Big Data and Translation.  All students on this programme will receive training in computational biology, mathematical biology and statistics to equip with the quantitative skills in tackling complex biological questions.  In the 1st year, students will carry out 3 rotation projects prior to selection of the final PhD project.

The lack of robustly validated drug targets has proved a significant barrier to the discovery of new treatments for malaria. Furthermore, target deconvolution studies with active compounds emerging from phenotypic screens against Plasmodium falcipariumhave confirmed that the same relatively few molecular targets are being hit repeatedly. The failure to identify new and exploitable drug targets through phenotypic screening is, in part, due to the limited chemical space represented in most large-scale compound libraries. Our strategy to combat this issue is to take advantage of the diverse chemistry represented by natural products to identify novel drug targets in these parasites. This approach has been successfully employed with the target of the fungal metabolite cladosporin confirmed as lysyl-tRNA synthetase (KRS) in P. falciparum [1]. Potent and selective inhibitors of KRS are now being developed. In the current study, we will utilise the high quality natural product libraries of our long-term collaboratorsand other novel chemical entities. Thesecompounds will be screened against P. falciparumin vitroand active compounds will then be submitted for target deconvolution studies. The principal molecular target(s) of active natural products will be determined using a number of orthogonal approaches including high-throughput genomics, cell biology/biochemistry and chemical proteomics. This study enable students to develop skills in the in vitroculture of P. falciparum, genetic and biochemical manipulation ofthe parasite and; chemical proteomics. They will also will offer students the opportunity play a significant role in the development of new therapeutics for the world’s largest parasitic killer.

[1] Baragana et al., Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis. Proc Natl Acad Sci U S A, 2019. 116: 7015-7020.

Recent work from the lab can be found in the following references:

Wyllie, S., et al., Cyclin-dependent kinase 12 is a drug target for visceral leishmaniasis.Nature, 2018. 560: 192-197.

Wall, R.J., et al., Clinical and veterinary trypanocidal benzoxaboroles target CPSF3.Proc Natl Acad Sci U S A, 2018. 115: 9616-9621.

Corpas-Lopez, V., et al., Pharmacological Validation of N-Myristoyltransferase as a Drug Target in Leishmania donovani.ACS Infect Dis, 2019. 5: 111-122.