In a study published in Nature Chemistry, they show that blocking the activity of an enzyme called N-myristoyltransferase (NMT) in the most common malaria parasite prevents mice from showing symptoms and extends their lifespan. The team are working to design molecules that target NMT more potently, and hope to start clinical trials of potential treatments within four years.
A recent study estimated that 1.2 million people died from malaria in 2010. Although a variety of antimalarial drugs are available, some strains of the parasite are resistant to treatment. These strains are becoming more common, with treatment failures reported across multiple frontline drugs. If acute illness is cured, the parasite can remain dormant in the blood and return to cause illness later. Malaria vaccines have been researched intensively, but none have been introduced into clinical practice.
A mature Plasmodium malariae schizont within an infected red blood cell.
Image: Centers for Disease Control and Prevention, Dr Mae Melvin
Using novel chemical tools, developed with funding from BBSRC, to study the post-translational modification of proteins in live parasite cells, the team showed that NMT is involved in a wide range of essential processes in the parasite cell. For example, in the production of proteins which enable malaria to be transmitted between humans and mosquitoes, and proteins that enable malaria to cause long-term infection.
This is the first compelling evidence that NMT is a druggable target against the most important human malaria parasite, Plasmodium falciparum.
The researchers have tested a handful of molecules that block the activity of NMT in the parasite living inside human red blood cells, and in mice, but further refinement will be needed before a treatment is ready to be tested in humans.
Dr Ed Tate, a former BBSRC David Phillips Fellow, who led the project from Imperial’s Department of Chemistry, said, “The drug situation for malaria is becoming very serious. Resistance is emerging fast and it’s going to be a huge problem in the future.
“Finding an enzyme that can be targeted effectively in malaria can be a big challenge. Here, we’ve shown not only why NMT is essential for a wide range of important processes in the parasite, but also that we can design molecules that stop it from working during infection. It has so many functions that we think blocking it could be effective at preventing long-term disease and transmission, in addition to treating acute malaria. We expect it to work not just on Plasmodium falciparum, the most common malaria parasite, but the other species as well.
“We need to do some more work in the lab to find the best candidate molecule to take into clinical trials, but hopefully we’ll be ready to do that within a few years.”
The discovery is the culmination of a five-year project by a consortium of researchers from Imperial College London, the MRC National Institute for Medical Research, the University of Nottingham, the University of York, and Pfizer, funded by BBSRC, the Engineering and Physical Sciences Research Council, and the Medical Research Council.
Notes to editors
Validation of N-myristoyltransferase as an antimalarial drug target using an integrated chemical biology approach. Nature Chemistry DOI: 10.1038/nchem.1830
Dr Edward Tate, Imperial College London
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