Protein kinases, cell signalling and differentiation.

Funding: Wellcome Trust (2016-2021)

Leishmania species are parasitic protozoa that are the causative agents of a spectrum of diseases, the leishmaniases. Little is known about the signalling pathways that regulate key events in the parasite’s life cycle and which protein kinases are essential and therefore potentially amenable to chemotherapeutic modulation. To address this we will perform loss-of-function genetic screens in Leishmania mexicana to identify genes involved in signalling pathways regulating parasite differentiation during transition between animal and sandfly hosts. It is expected that some genes will also be identified that are essential for proliferation and survival of Leishmania once an infection is established in the mammalian host. The expected output of the project will be novel insights into protein kinase function in Leishmania and a holistic overview of cell signalling pathways that will integrate into ongoing “omics” analyses within the Leishmania community.

Drug discovery

Funding: MRC, GCRF

Partners: GSK, Novartis, Ubiquigent, UbiQ

 

In recent years, drug discovery for leishmaniasis has focused on phenotypic screening approaches. Whilst several promising anti-leishmanial compounds have been identified and developed into pre-clinical candidates, complementary approaches are required to provide an alternative entry point for medicinal chemistry. Target-based drug discovery offers the opportunity to design potent and selective anti-parasitic compounds with a well-defined mechanism of action, which could provide safe, effective, affordable and convenient treatments to replace the inadequate treatment options for leishmaniasis.  We are taking both genetic and chemical approaches to validate enzymes involved in post-translational modifications, with a focus on protein kinases, peptidases and epigenetic regulators. These are a promising group of enzymes for structure-based drug discovery for the following reasons. (a) Many enzymes involved in post-translational modifications are druggable (b) FDA approved drugs are in the market (c) Pharmaceutical companies have extensive experience of developing specific inhibitors against these target classes (d) Expertise can be used for anti-leishmanial drug discovery when appropriate targets and lead compounds have been identified.

Peptidases, cellular remodelling and host-parasite interaction

Funding: MRC, MRC Newton

The Leishmania parasite undergoes considerable cellular remodelling during its life cycle.  This programme of research aims to characterise the key biological processes involved in protein turnover and protein processing in Leishmania, which may allow the identification of potential drug targets and virulence factors. Our study focuses on key biological processes of Leishmania that are distinct from those in mammals and so offer opportunities for therapeutic exploitation. The research extends our past analyses of the multiple roles of peptidases and other virulence factors in Leishmania infection and pathogenicity, which have highlighted key and unusual biological processes:

  •  The cellular remodelling processes that lead to the development of infectious parasites and transformation within the mammalian host, including the occurrence and molecular mechanism of autophagy and the ubiquitination pathway.

  • The crucial role of the parasite’s endosomal and lysosomal pathways in interactions with the mammalian host, and the route of intracellular trafficking of key virulence factors, including natural peptidase inhibitors.

  • The extensive chromosome and gene copy number variation in strains and species of Leishmania.

Please reload

Department of Biology
University of York

Heslington, York, YO10 5DD, UK 

jmottramgroup@gmail.com