Partnership speeds malaria and leishmaniasis drug discovery

24 April 2012

Malaria parasites develop and multiply inside red blood cells, burst out and invade new red blood cells

Image: Malaria parasites develop and multiply inside red blood cells, burst out and invade new red blood cells©  Dr Mary Kneupfer

Scientists at the MRC's National Institute for Medical Research (NIMR; now part of the Francis Crick Institute) have worked with colleagues from Imperial College London, the universities of Nottingham and York and the drug company Pfizer to find new drug candidates for the tropical diseases malaria and leishmaniasis. The collaboration is hoped to speed up the development of treatments for these devastating tropical diseases.

Leishmaniasis and malaria are caused by different protozoan parasites that are spread by sandflies and mosquitoes. Leishmania protozoa cause a range of diseases associated with immune dysfunction - from disfiguring skin lesions to the often fatal 'black fever', where the parasite attacks a patient's internal organs.

Up to two million cases of leishmaniasis occur in 88 countries every year. The first-line drugs that have been used since the 1930s are toxic and resistance to them is increasing, particularly in India. Significant progress towards new treatments has been made in the past 10 years, but resistance is still a problem.

Malaria is one of the most devastating diseases in the developing world - recent reports showed it caused between 650,000 and 1.2 million deaths in 2010 alone. The most commonly used drugs are also failing rapidly due to resistance. Although there are some alternatives, these are expensive and the threat of resistance is ever present, meaning new, cheaper drugs are urgently needed. There are no vaccines for malaria or leishmaniasis.

For all protozoa to survive, they need an enzyme called N-myristoyl transferase (NMT). Previous research in African sleeping sickness, another protozoan disease, showed that targeting NMT and stopping it from working kills the parasites and stops the disease. This makes NMT an excellent drug target.

In this study, the consortium screened Pfizer's candidate drug library of 150,000 compounds against the NMT of the protozoa responsible for most cases of leishmaniasis (Leishmania donovani) and malaria (Plasmodium falciparum).

They found four series of compounds that inhibited Plasmodium falciparum NMT. However these showed a strong overlap against human NMT, meaning that the compounds will only be useful if it can be shown that they don't have any toxic effect on human cells.

Nevertheless, the team did find two new series of compounds that inhibited only Plasmodium falciparum and two that were selective for Leishmania donovani NMT. These four 'hits' provide an excellent starting point for further drug discovery work. The structures of the most promising compounds have been published, to stimulate additional work in this area.

Tony Holder, who led the work for NIMR, summarised: "This 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."

The paper, ' Selective Inhibitors of Protozoan Protein N-myristoyltransferases as Starting Points for Tropical Disease Medicinal Chemistry Programs', was published inPLOS Neglected Tropical Diseases.

  • NIMR scientists teamed up with researchers at Imperial College London, the Universities of Nottingham and York and the drug company Pfizer to look for new drugs for malaria and leishmaniasis
  • These diseases are caused by protozoan parasites and lead to huge numbers of illnesses and deaths every year, mostly in developing countries. For both, new drugs are urgently needed due to resistance to old treatments
  • The collaboration revealed some possible compounds to target the protozoa that cause each disease, which will hopefully accelerate the discovery of new drugs