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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.

Interplay of phosphorylation and ubiquitination regulating Leishmania differentiation
Funding: Wellcome Trust (2022-2027)

The life cycle of the Leishmania parasite requires transition between insect and mammalian hosts, where temporal cell type differentiation allows adaptation to changing environments. Over the last few years we have identified a number of Leishmania protein kinases and ubiquitination enzymes that are essential for successful differentiation and establishment of infection, regulating cell signalling and cellular remodelling. We will now tackle two fundamental processes that are fundamental to the parasite’s biology: The regulatory mechanism(s) that control cellular remodelling during differentiation and the requirement of co-regulation of the cell cycle and differentiation to enable establishment of infection To address this we will decipher the protein kinase-dependent signalling pathways controlled by activators and repressors intrinsic to successful differentiation, as well as the signalling pathways regulating kinetochore assembly during differentiation-induced re-initiation of the cell cycle. We will investigate cellular remodelling through characterisation of E3 ubiquitin ligases essential for differentiation. These studies will lay the foundations for developing proteolysis targeting chimeras and protein kinase tool compounds for investigating Leishmania biology and for drug discovery. The expected output of the project will be novel insights into the cross-talk between cell signalling and cellular remodelling through the co-ordinated action of phosphorylation and ubiquitination post-translational modifications.

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