Scientists identify nicotinamidase enzyme as new drug target for Leishmaniasis

Oct 29 2011

Leishmaniasis is a serious parasitic disease with several forms, cutaneous mucocutaneous or visceral, respectively causing skin sores, ulceration and internal damage. The visceral form can be fatal if no treatment is given. These diseases are endemic in more than 98 countries across the world, most of them developing countries, and 350 million people are exposed to them. The protozoan pathogens, responsible, from the genus Leishmania, are transmitted to humans or other mammals by the bite of a sand fly, Phlebotomus. Medications exist, including antimony, the one most commonly used, but their efficacy is diminishing owing to the emergence of resistant parasites.

Nevertheless new hope is on the horizon for treating this much-neglected disease. IRD scientist and their research partners recently identified the key role of nicotinamidase, an enzyme in the parasite Leishmania, essential for its survival but which does not exist in humans. The pathogen is incapable of developing in mammals In the absence of this enzyme. Specific targeting of this enzyme could lead to more effective ways of controlling this neglected tropical disease.

Leishmaniasis is a much-neglected tropical disease, in a similar way to Chagas disease or sleeping sickness. Without treatment, the most severe form of the parasitic infection generated -visceral leishmaniasis- proves fatal. The different forms affect 16 million people  in the world, mainly in the developing countries. The options for treatment are often dictated by cost. For this reason the relatively inexpensive antimony derivatives are the most commonly used antileishmanials, aside from their efficacy. However, their curative effect is weakening owing to the emergence of resistant strains. It is becoming urgent to develop new, inexpensive antileishmanial agents that are more effective and have low toxicity.

Outdated treatments

The medications currently used present a whole combination of drawbacks. Treatments are long, toxic and relapse is highly common. Most of them date back to research conducted in the 1950s. In India, the situation is becoming critical following the emergence of resistant strains of the parasite, where in some regions, failure of classic treatments can be as high as 60 % in patients who have never previously been treated. In this context, control of the endemic parasitic disease depends on the discovery of new means of prevention and treatments, affordable for the people concerned. Scientists are developing various measures for developing a vaccine for humans and devise the medications of the future.

New approach, new drug target

The classical way of searching for antiparasitic drugs consists in using in vitro techniques to screen the antiparasitic activity of natural substances or medications initially applied for a completely different use. Thus the active molecules against leishmaniasis have previously been isolated from natural plant substances, like quinolines.

A new therapeutic pathway is being traced thanks to a new approach. While seeking the nutritional factors which enable Leishmania to adapt to the host's internal environment, IRD researchers and their partners characterized a new therapeutic target: an enzyme, nicotinamidase, which plays a key role in the parasite's cellular development. The research team identified this compound in Leishmania and demonstrated its importance for the pathogen's survival. Nicotinamidase enables it to assimilate vitamin B3 (nicotinamide), essential for the synthesis of a substance vital for all cells, NAD+. And, crucially, this enzyme does not occur in mammals, thereby precluding any risks of cross-activity in humans. Joint research with a structural biochemistry team in Montpellier was successful in determining the structure of this enzyme isolated from the parasite. This has opened the way for chemists to synthesize specific inhibitors of that enzyme that will hold back the parasite's proliferation in the host.

Four of the five continents affected

Leishmaniasis is transmitted by a single bite from its vector, the sandfly Phlebotoma. It comprises three different forms: cutaneous, mucocutaneous and visceral, the most serious. These parasitic infections rage over extensive areas of the globe, affecting 98 countries, in all parts of the world, except Oceania, and 350 million people are exposed to the risk of contracting it. An estimated 2 to 2.5 million new cases arise each year, of whom 500 000 people are struck by the visceral form of the disease.

Dogs and wild Canidae are the major reservoirs of this disease which is rife mainly around the Mediterranean Basin. In these areas, strongly endemic for canine leishmaniasis, incidence in humans nevertheless remains quite low. The disease is an increasingly important problem in Southern Europe with the spread of the AIDS pandemic and a growing number of Leishmania/HIV co-infections occurring. But the cause for concern is even more extreme for public health in other parts of the world. Especially so in India, Brazil and the Sudan (zones endemic to L. donovani/chagasi), where the past few decades have seen fatal epidemics leaving thousands of victims.

These new investigations have brought new hope of treatment for the several million sufferers. Nicotinamidase, the enzyme the research team characterized and absent from mammals, turns out to be particularly promising for more effectively fighting this neglected tropical disease. Scientists will now be better armed to develop inhibitors that specifically target Leishmania and, more generally, the other parasites of the Trypanosomatidae family.