Inhibitors of Kinetoplastid Sphingolipid Synthases as Potential Therapeutic Agents


The protozoan kinetoplastid parasites Leishmania spp, Trypanosoma brucei and Trypanosoma cruzi are responsible for potentially fatal diseases that affect over 22 million people worldwide, with an estimated 450 million at risk. Current therapies are expensive and not widely accessible. In addition, drug toxicity and emerging resistance are major concerns. Previous work has identified the essential kinetoplastid sphingolipid synthase (SLS) as an attractive pharmaceutical target due to the divergence of function compared with the mammalian orthologue. A high-throughput compatible screening assay was developed to test the 1.8 million compound library held at GlaxoSmithKline in Tres Cantos against the Leishmania major enzyme. The 19,669 compounds identified were subjected to further screening to identify those which were highly active yet selective for the parasite enzyme. 216 of these compounds proved to be hits and were subsequently tested on Leishmania promastigotes and amastigotes (the insect and mammalian stages of the parasite respectively), infected macrophages, HepG2 cells (a human liver cell line) and biochemically against the L. major enzyme. The results were encouraging, with several compounds displaying high activity against the parasites whilst having a negligible effect on the human cells. A set of promising chemical scaffolds has subsequently been identified and are presently being evaluated in murine models. Current and future work centres around redesign and resynthesis of these compounds in order to produce the best possible lead candidates.

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