Abstract
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/non-governmental organisations such as Medical Research Council and Wellcome Trust can stimulate research for neglected diseases.
Highlights
Protozoan parasites are major causative agents of global infectious diseases that affect millions of people in tropical and sub-tropical regions of the world [1]
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 (HsNMT1 and HsNMT2) and for broad-spectrum antiprotozoan activity against the NMT from Trypanosoma brucei
Summary
Protozoan parasites are major causative agents of global infectious diseases that affect millions of people in tropical and sub-tropical regions of the world [1]. In the absence of effective vaccination strategies, treatment for many of these infections depends on chemotherapy and is reliant on ‘‘old’’ drugs that have often been in use for long periods; were originally developed for other types of disease; give rise to increasing levels of microbial resistance; and often show unacceptable levels of toxicity. 1.5–2 million new cases each year in 88 countries around the globe, with 350 million people at risk and a disease burden of ,2.4 million disability-adjusted life years [2,3]. Pentavalent antimonials have been the first-line treatment for VL since the 1930s but these compounds are toxic, with resistance an increasing problem in the Indian sub-continent [4].
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