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 leishmaniasisoccur 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 inhibitedPlasmodium 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.