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Date: June 22 (Friday), at 3 p.m. - Place: Auditorio "Ines Joekes"
Title: ""Drug discovery for kinetoplastid diseases; challenges and opportunities in Chagas' disease and development of two new pre-clinical candidates for visceral leishmaniasis".
Speaker: Dr. Manu De Rycker - Drug Discovery Unit, Dundee University, Dundee, UK
Responsible: Prof. Luiz Carlos Dias, Ph.D."
Abstract: The Drug Discovery Unit at the University of Dundee and the GlaxoSmithKline Kinetoplastid Discovery Performance Unit, with support from the Wellcome Trust, have formed a long-term partnership to conduct drug discovery within kinetoplastid diseases. This collaboration has made significant progress, highlighted by the identification of two new oral pre-clinical candidates for visceral leishmaniasis (VL). Here we describe the initial identification of both series through transitioning active series from Trypanosoma brucei and Trypanosoma cruzi programmes into VL active series. Both series were profiled extensively in a panel of in vitro Leishmania assays including promastigote, axenic amastigote and intracellular assays as well as rate-of-kill and clinical isolate assays, an effort which helped us develop our Leishmania screening cascade. In addition we have demonstrated that both series work through different modes of action. A short overview of both lead-optimisation campaig ns will demonstrate how for both series a focus on balancing potency and solubility delivered compounds with candidate-level properties. Current standard of care for VL suffers from multiple issues (lack of efficacy, safety, drug resistance, stability, cost, parenteral administration only) and community-wide there is a limited pipeline for VL. The two new chemical series presented here are a significant step forward towards the development of new oral drugs for visceral leishmaniasis and open avenues towards combination treatment.
In addition to our work in visceral leishmaniasis we have been working together to understand the properties required for new Chagas’ disease drugs. Following efficacy studies with multiple new series we have identified three key aspects: compound mode of action, parasite localisation and compound distribution. We will present results from recent in vivo and in vitro experiments addressing these points and how they are affecting our approach to identifying and developing new leads. We will present combination therapy options as one way to overcome the challenges presented by Chagas’ disease.
This work illustrates the substantial benefits that working in an academic-industry partnership brings for the development of new drugs for neglected diseases.