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  • Final Activity Report Summary - NEW ABCS IN LEISHMAN (Functional and biochemical characterisation of novel ABC transporters of biomedical interest in the protozoan parasite Leishmania)
FP6

NEW ABCS IN LEISHMAN Streszczenie raportu

Project ID: 513607
Źródło dofinansowania: FP6-MOBILITY
Kraj: Spain

Final Activity Report Summary - NEW ABCS IN LEISHMAN (Functional and biochemical characterisation of novel ABC transporters of biomedical interest in the protozoan parasite Leishmania)

Diseases produced by protozoan parasites threat the lives of nearly one-third of the human population worldwide. Among them, leishmaniasis and sleeping sickness are the major cause of mortality after malaria. Drugs used to treat these diseases are limited, toxic and obsolete, and therefore, there is an urgent need for developing new drugs. Current situation is complicated by the emergence of resistance to conventional drugs. The recent completion of the trypanosomatid genome projects has shown an important number of new proteins that could be involved in drug resistance and/or be potential new pharmacological targets. The aim of this project is to characterise a family of such proteins, the ATP-binding cassette (ABC), in the trypanosomatid parasites responsible for these diseases, Leishmania and Trypanosoma brucei. After a carefull analysis of the genome of this trypanosomatids, we have selected three groups of genes for further analysis.

The first one is composed by members of the ABCG subfamily. In humans, homologous genes have an enormous clinical relevance as they include members involved in multidrug resistance during the treatment of cancer, and others involved in the regulation of lipid metabolism. At the moment we have not detected any role of these trypanosomatid genes in parasite drug resistance. However, interesting phenotypes have been observed when these genes are over- or down-expressed. In Leishmania, our results suggest that one of them plays a role in the translocation of Phosphatidyl-serine (PS). Its physiological implication could be very interesting: PS is usually located in the inner leaflet of the parasite plasma membrane, but it has to be translocated to the outer leaflet for the infection of the mammalian cells (macrophages). Indeed, differences in the amount of surface PS molecules correlate with the infectivity of the parasite, and compounds that bind PS diminish the ability of Leishmania to infect macrophages. We are currently trying to determine the role of this ABCG in the infection process. In the case of T. brucei, we have observed opposite phenotypes caused by the reduction in the expression of some of these ABCG genes. For one of them, we found a reduced growth, suggesting that this gene could be important for the viability of the parasite. For other two genes, the decrease of their expression resulted in an increased growth rate. We will study how these behaviours affect the biology of the parasite and their ability to develop the disease experimentally using murine models.

We are currently initiating the study of a second group of selected ABC genes. It is formed by genes with have no homologous ones outside the trypanosomatid family. If they play essential roles in the parasite, they will be very interesting as drug targets, as they do not present homology with human proteins. In addition, the homology between them is very low (less than 15 % of similarity), so they do not belong to the same subfamily. As these parasites present many evolutionary novelties at molecular, biochemical and cellular level, we can expect to obtain new information that will contribute to advance our knowledge on the biology of these and related organisms.

Finally, we have continued the characterisation of Leishmania MDR1, an ABC transporter involved in resistance to miltefosine, the first orally active drug approved for the treatment of leishmaniasis. We have shown that miltefosine resistance is due to a LMDR1-mediated ability to efflux the drug, leading to a reduction in the intracellular miltefosine accumulation. LMDR1 modulation might be an efficient way to overcome this kind of resistance.

Our results have shown that a combination of inhibitor subdoses targeting different domains of LMDR1 efficiently overcomes parasite miltefosine resistance by inhibiting drug efflux. This cocktail of inhibitors does not produce any side effect in different mammal cell lines. In addition, we have observed that sitamaquine, another orally active drug currently used in clinical trials for the treatment of leishmaniasis, is also a very efficient inhibitor of LMDR1.

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CONSEJO SUPERIOR DE INVESTIGACIONES CIENTIFICAS
18100 ARMILLA-GRANADA
Spain
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