Poster presentation by Daniel Harris at the 21st Royal Society of Chemistry – Medicinal Chemistry Symposium (13 – 15 September 2021, Cambridge UK). 

Title: A ubiquitin activating enzyme as a novel therapeutic target for leishmaniasis.

Daniel Harris (1), Dr Mads Gabrielson (2), Dr Boris Rodenko (3), Dr Farid El Oualid (3), Prof Jeremy Mottram (4), Dr Danny Huang (2), and Dr Richard Burchmore (1).

1. University of Glasgow, Scotland.
2. Beatson Institute for Cancer Research, Scotland.
3. UbiQ Bio BV, The Netherlands.
4. University of York, England.

Abstract: Leishmaniasis is a neglected tropical disease, which inflicts a variety of gruesome pathologies on humans. The number of individuals afflicted with leishmaniasis is thought to vary between 0.7 and 1.2 million annually, of whom it is estimated that 20 to 40 thousand die. Current leishmaniasis treatments are inadequate due to toxicity, cost, and ineffectiveness, so there is an urgent need for improved chemotherapies. Leishmania parasites modulate protein levels in a developmentally coordinated pattern as they move through their digenetic life cycle. Protein ubiquitination regulates protein turnover in many organisms, in part by targeting proteins for degradation. Using bioinformatic and mass spectrometric methods, Daniel Harris and colleagues have identified key enzymes in Leishmania’s ubiquitin conjugation system, in both major stages of the parasite’s life cycle. A key enzyme was recombinantly generated in a functional form, and a protein-ligand structure was solved through protein crystallography, with a complementary structure determined using small-angle X-ray scattering. This structure has been used to explain the inhibitory potency of various inhibitors, and selective inhibitors of the parasite enzyme have been identified. Furthermore, an interactome of this novel drug target was generated and its substrates were catalogued.