Targeting and exploiting the proteasome in anti-parasitic drug discovery

Dr Manu De Rycker; University of Dundee

Manu De Rycker is a Principal Investigator at the University of Dundee, UK. He is the Head of Translational Parasitology and Kinetoplastid Drug Discovery at the University’s Drug Discovery Unit. Manu obtained a PhD in molecular genetics from the University of Cincinnati, Ohio, USA and following postdoctoral work at the Cancer Research UK London Research Institute, he moved to the University of Dundee in 2009. Manu heads the team that develop and run cell-based assays for the parasitology programmes in the DDU. The team has successfully built extensive screening cascades for Leishmania donovani and rypanosoma cruzi that comprise high-throughput primary screening assays as well as advanced secondary assays with high physiological relevance. As Portfolio Leader for Kinetoplastid Drug Discovery Manu leads a substantial drug discovery programme focused on delivering new pre-clinical candidates for  isceral leishmaniasis and Chagas disease. In collaboration with GSK this programme has developed two new clinical candidates for visceral leishmaniasis.

Visceral leishmaniasis is a deadly disease caused by the protozoan parasite Leishmania donovani and is prevalent in Asia, Africa and Latin America. In this presentation I will focus on the development of our clinical candidate that acts through inhibition of the parasite proteasome. I will describe its discovery and give a short overview of the lead-optimisation campaign to demonstrate how a focus on balancing potency and solubility delivered compounds with candidate-level properties. I will also cover cryo-EM studies and the molecular basis for selectivity over the human proteasome. In a second section I will discuss how we enabled proteasome drug discovery for Chagas disease, caused by the related parasite Trypanosoma cruzi, through recombinant expression of the parasite proteasome. Generation of various mutant recombinant proteasomes proved essential to understand compound inhibition profiles and proteasome substrate selectivity. Finally, I will briefly discuss how we seek to develop targeted protein degradation approaches for parasitic diseases. Our work highlights the benefits of industry-academia partnerships and shows that with the right expertise, academic drug discovery can deliver new treatments for highly neglected patient populations.