Identifying and utilising new antileishmanial drug targets

Leishmaniasis is a vector-borne Neglected Tropical Disease, caused by protozoan parasites of the genus Leishmania. Current treatments are challenged by toxicity, difficult modes of administration and growing resistance. Consequently, there is an urgent need to develop a drug with a novel mode of action.
Our group has identified the Leishmania major inositol phosphorylceramide synthase (LmjIPCS) as a potential drug target. This membrane-bound enzyme is involved in sphingolipid biosynthesis, and with no mammalian orthologue provides access to selective drugs. A library of 1040 bioactive compounds was screened against LmjIPCS and the most active were tested against the parasite. From these screens the over-the-counter antihistamine clemastine was selected as the most promising compound to develop further. An in vivo study of clemastine has shown a significant reduction in parasite burden when given intralesionally.
This presentation will share these findings together with details of synthetic studies towards new active and more accessible analogues.