Targeting one enzyme is the key to tackling two tropical diseases

A way to combat malaria developed at Imperial may also be effective against the deadly tropical disease leishmaniasis, new research has shown.

The approach targets a crucial enzyme which causes the parasite to shut down and eventually die following infection. In the latest research, researchers from Imperial College London and the University of York found that blocking the same enzyme in the Leishmania donovani parasite also has a devastating effect on this pathogen. The study is the cover story in this month’s Chemistry and Biology.

30,000 people each year

Leishmaniasis is a tropical parasitic disease spread by sand flies when they feed on human blood, with around 300 million people at risk of infection across north Africa, southern Europe, the Middle East, the Indian sub-continent and Central and South America.  The most deadly form of the disease is caused by the parasite Leishmania donovani and kills 30,000 people each year.

“There are many groups around the world working on malaria, but there is much less activity on leishmaniasis, despite it causing a high burden in disadvantaged communities,” says Professor Ed Tate, who led the research at Imperial. “The drugs currently available have problems with toxicity and resistance, as well as being expensive.”

In 2013, research by Professor Tate’s group, reported in Nature Chemistry, showed that an enzyme called NMT was central to numerous crucial protein functions in the malaria parasite.

They also designed a number of different molecules to inhibit the enzyme, which prevented the parasite from multiplying and extended the lifespan of infected mice.

NMT was first identified as a target for drug development in leishmaniasis in 2003 by Professor Deborah Smith, then at Imperial and now at the University of York. In this latest study, the team identified which proteins in the Leishmania parasite were affected by the enzyme, and then quantified the effect that NMT inhibitor molecules had on these proteins.

“Relatively little was known about these molecular pathways in this parasite and this rigorous approach allowed us to really dig down to find out more about how it works and – for the first time – quantify the potential of NMT inhibitors as drug candidates,”  said co-author, Dr Megan Wright.

“NMT is a very central drug target,” continued Professor Tate. “If you stop it from working, the whole parasite shuts down and dies. We now have the evidence that links the drug-like compounds to their effect on the enzyme and the death of the parasite. We had long suspected that inhibiting this enzyme could be key to tackling other devastating parasitic diseases, so it’s particularly pleasing that this seems also to be the case for leishmaniasis.”

The team intends to further improve its drug compound portfolio ahead of animal trials, which they hope to take place within 3 years.

The research was funded by The Wellcome Trust and the Engineering and Physical Sciences Research Council, with additional support from the European Union, the Medical Research Council, and the Biotechnology and Biological Sciences Research Council.

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Study reference: “Global Analysis of Protein N-Myristoylation and Exploration of N-Myristoyltransferase as a Drug Target in the Neglected Human Pathogen Leishmania donovani,” Chemistry and Biology, corresponding authors Ed Tate and Megan Wright.