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New hope for treating malaria

Researchers at the University of Leeds in the UK have developed chemicals which kill the most deadly malaria-causing parasite, including those resistant to existing drugs

Researchers at the University of Leeds in the UK have developed chemicals which kill the most deadly malaria-causing parasite, Plasmodium falciparum – including those resistant to existing drugs.

The compounds work by preventing the enzyme dihydroorotate dehydrogenase (DHODH) - essential to the growth of the parasite - from working, resulting in its death. 

"Without this enzyme, Plasmodium falciparum is unable to grow and therefore it dies. The inhibitors developed at Leeds bind to the DHODH enzyme in the parasite and stop it functioning, preventing the proliferation of the parasites, which live in red blood cells. In addition, our chemicals are equally effective against parasites that have developed resistance to drugs," says lead researcher, Dr Glenn McConkey, from Leeds' Faculty of Biological Sciences.

He adds: "DHODH in humans is not an essential enzyme, so by concentrating our studies on it we can develop chemical inhibitors that have a negative impact on the parasite without any major side effects to the human host. In effect, we are exploiting a biological difference, and this will allow us to develop potent, selective inhibitors."

"Our chemicals are particularly exciting as they kill malaria parasites at low concentrations, something that is important for medicines as they are massively diluted on entering the bloodstream and, unlike many pharmaceutical products, we have a firm understanding of the molecular basis of their action. This project highlights the benefits of combining biological and chemistry disciplines." 

The next stage is to develop a larger collection of potent inhibitors and to see how these work alongside commonly-used treatments. 

The paper, "Structure-Based Design, Synthesis, and Characterization of Inhibitors of Human and Plasmodium falciparum Dihydroorotate Dehydrogenases", published in the Journal of Medicinal Chemistry, was supported in part by a World Health Organisation tropical diseases research grant and a grant from Medicines for Malaria Venture. 

22nd April 2009

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