Authors

S K Menzies¹; G J Florence¹; T K Smith¹;  ¹ University of St Andrews

Discussion

We report the characterisation of the secondary alternative oxidase (AOX2) as a novel drug target in the trypanosomatids.  The trypanosome alternative oxidase (TAO) has been well characterised as a drug target in T. brucei, but it is absent from T. cruzi and Leishmania spp.  However, the previously un-investigated AOX2 is present in the three human-infective trypanosomatids and has no mammalian orthologue, thus making it an attractive potential kinetoplastid specific drug target.  We report evidence that AOX2 is an essential mitochondrial protein in T. brucei, T. cruzi and L. major, and is involved in mitochondrial respiration.  Furthermore, we have successfully purified recombinant AOX2 and confirmed its function as an iron-dependent ubiquinol oxidase.  We are screening for selective inhibitors of the AOX2 using our in-house natural product-like library and a fragment library to identify lead compounds.