The lack of robustly validated drug targets in Leishmania spp. is a major impediment to the discovery of new drugs and effective treatments for leishmaniasis. Here, 6 phenotypically-active anti-leishmanial compounds were selected from GSKs Kinetobox compound collections for subsequent target deconvolution studies. The principal aim of these studies was to identify molecular targets that can be exploited by subsequent target-focused anti-leishmanial drug discovery. Using multiple orthogonal genome-wide genetic, chemical proteomic and biochemistry-based approaches, two compounds were found to target novel anti-leishmanial targets, namely oxidosqualene cyclase, a key enzyme of sterol biosynthesis, and Sec23, a component of the COPII coatomer, a vesicular coat protein involved in vesicular trafficking and secretion. Future studies to further investigate and exploit these novel targets are discussed. Remarkably, three of the four remaining compounds studied were confirmed as chelators of divalent metals. Compounds acting via this generic and potentially toxic mechanism of action are not considered progressible for drug discovery. Therefore, the significant number of chelators identified in this random selection of the Kinetobox is concerning and may be indicative of high levels of chelators more generally in screening libraries. Strategies to identify chelators at an early stage of the drug discovery process are proposed.
|Date of Award
|Medical Research Council & GlaxoSmithKline
|Susan Wyllie (Supervisor) & Ian Gilbert (Supervisor)