Leishmaniasis is a Neglected Tropical Disease (NTD) caused by the protozoan Leishmania spp. Over 350 million people worldwide are at risk, with an estimated annual death toll of 60,000  . Treatment typically requires long, expensive courses of exposure to toxic medicines via parenteral administration. There is an urgent need for novel treatments  that are inexpensive and free of side effects.Our group has previously identified and validated the Leishmania major inositol phosphorylceramide synthase  (LmjIPCS) enzyme as an attractive drug target.1,2 This membrane-bound essential  enzyme has no mammalian equivalent, potentiating the development of safe  , selective  anti-leishmanials.A set of 1200  pharmacologically active compounds (NINDS set supplied by MRCT) were screened against LmjIPCS, 57  were found to exhibit >70%  inhibition at 20 �M. A secondary assay against L.major promastigotes highlighted 14  compounds with selective  cytotoxic effects. Four  of these inhibitors displayed ED50 values lower than that of pentamidine (2.05 �M), a second-line treatment for leishmaniasis. Significantly these compounds have good bioavailability  and mammalian safety profiles  , making them ideal for development into new drugs. A hit-to-lead   study is being explored to elucidate further structure-activity relationship data  . This approach has the scope to provide a wide variety of chemical tools  that will deliver potent  , selective  leishmanicidal therapies.References:   (1) P.W. Denny, H. Shams-Eldin, H.P. Price, D.F. Smith, R.T. Schwarz, J. Biol. Chem., 2006, 281  , 28200- 28209; (2) J.G. Mina, J.A. Mosely, H.Z. Ali, H. Shams-Eldin, R.T. Schwarz, P.G. Steel, P.W. Denny, Int. J. Biochem. Cell Biol., 2010, 42  , 1553-1561.

Inhibitors of <i>Leishmania major</i> inositol phosphorylceramide synthase: New therapies for leishmaniasis

248th National Meeting (2014)

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Inhibitors of Leishmania major inositol phosphorylceramide synthase: New therapies for leishmaniasis