Inhibition of N-myristoyltransferase has been validated pre-clinically as a target for the treatment of fungal and
trypanosome infections, using species-specific inhibitors. In order to identify inhibitors of protozoan NMTs, we chose to
screen a diverse subset of the Pfizer corporate collection against Plasmodium falciparum and Leishmania donovani NMTs.
Primary screening hits against either enzyme were tested for selectivity over both human NMT isoforms (Hs1 and Hs2) and
for broad-spectrum anti-protozoan activity against the NMT from Trypanosoma brucei. Analysis of the screening results has
shown that structure-activity relationships (SAR) for Leishmania NMT are divergent from all other NMTs tested, a finding not
predicted by sequence similarity calculations, resulting in the identification of four novel series of Leishmania-selective NMT
inhibitors. We found a strong overlap between the SARs for Plasmodium NMT and both human NMTs, suggesting that
achieving an appropriate selectivity profile will be more challenging. However, we did discover two novel series with
selectivity for Plasmodium NMT over the other NMT orthologues in this study, and an additional two structurally distinct
series with selectivity over Leishmania NMT. We believe that release of results from this study into the public domain will
accelerate the discovery of NMT inhibitors to treat malaria and leishmaniasis. Our screening initiative is another example of
how a tripartite partnership involving pharmaceutical industries, academic institutions and governmental/nongovernmental
organisations such as Medical Research Council and Wellcome Trust can stimulate research for neglected
diseases