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P10001
Antimalarial Drug Discovery From Target Validation to Lead Qualification
Presenter Didier LeRoy, Merck Serono S.A., Switzerland
Additional Authors:
Malaria still remains the most deadly tropical disease affecting up to five hundred million people yearly and killing three million of them, mainly children in sub-Saharan Africa. The emergence of parasitic strains resistant to drugs used currently in chemotherapeutic treatments such as chloroquine or to the ones developed more recently like pyrimethamine, has a direct impact on both the incidence and the spreading of the disease. The difficulty to develop a vaccine and the limited number of new drugs reaching the clinical development status strengthens the urgent need for new molecules with different mechanisms of action.In vector-mediated diseases such as Malaria, the complexity of the host/parasite relationships is resulting from distinct phases within the infection process, each of them being potentially of therapeutic interest. Indeed, during the life cycle of Plasmodium faciparum, sporozoites are the infectious forms injected by the mosquito and that develops into human liver, whereas, merozoites (the invasive forms of the erythrocytes) and trophozoites (the forms multiplying in erythrocytes) are stages disseminating in the blood.
Modern drug discovery usually relies on efficient validation of potential targets and key screening strategies to optimize subsequent identification rate of high quality Hit/Lead molecules. Optimizing the success of antimalarial drug discovery requires a good biochemical understanding of target candidates thus facilitating the choice of an adequate molecular assay to be developed in view of the future HTS campaign. Similarly to human cells, parasite proliferation/viability is highly depending on specific signaling pathways involving kinases and phosphatases among other key proteins. Outside the kinase kingdom, protease-mediated protein degradation processes are of particular importance in parasite’s ability to penetrate host cells.
Within the last decade, interactions between academic laboratories aiming at fighting against neglected diseases and Lead discovery departments of pharma/biotech industries increased significantly and were strongly expected to generate major outcomes through synergistic collaborations. Here, we will describe how the structure of a private organization allows a smooth integration of anti-parasitic drug discovery projects into the normal project flow of the company and provides a wide panel of technologies, efficient progress plans and evaluation criteria for the qualification of new molecules. Finally we will explore new discovery approaches as potentially fruitful alternatives to target-based screening.