Science for Health
14 May 2012
A partnership between industry and academia has made available new selective inhibitors of protozoan N-myristoyl transferase to accelerate the development of drugs to treat malaria and leishmaniasis. The research is published in PLoS Neglected Tropical Diseases.
Tropical diseases caused by protozoan parasites, such as malaria, leishmaniasis and African sleeping sickness, remain entrenched in large parts of the world. For many patients safe treatments are not available and there is a pressing need for new therapeutics to be developed. Inhibition of the enzyme N-myristoyltransferase (NMT) has been validated pre-clinically as a target for the treatment of fungal and trypanosome infections.
A consortium of scientists based at Imperial College, the Universities of York and Nottingham, plus Tony Holder's lab at NIMR, has focused on the development of inhibitors of NMT in parasitic protozoa. Their latest work has been funded by an MRC Industry Collaboration Agreement (MICA) and the Wellcome Trust, and also included scientists from Pfizer. They have screened about 150,000 compounds, from the Pfizer Global Diverse Representative Set, against Plasmodium falciparum and Leishmania donovani. Primary hits were counter-screened for selectivity against human NMT isoforms and eight series of protozoan NMT inhibitors were identified, of which six showed good selectivity for either Plasmodium or Leishmania NMTs. These series may form the basis of medicinal chemistry programmes to develop drug candidates, and the structures of the most promising compounds have been published, to stimulate additional work in this area.
A collaboration between academic laboratories with validated drug targets and pharmaceutical companies with both large compound libraries and drug discovery expertise provides an ideal public-private partnership to accelerate drug discovery for neglected tropical diseases.
Overlay of structures of inhibitors based on alignment of binding site residues. The crystal structural information for NMTs from fungal, human and protozoan NMTs was used as the basis for modelling work.
Andrew S. Bell, James E. Mills, Gareth P. Williams, James A. Brannigan, Anthony J. Wilkinson, Tanya Parkinson, Robin J. Leatherbarrow, Edward W. Tate, Anthony A. Holder, Deborah F. Smith (2012)
Selective inhibitors of protozoan protein N-myristoyltransferases as starting points for tropical disease medicinal chemistry programs
PLoS Neglected Tropical Diseases 6(4): e1625 Full text.
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