Towards multi-stage drugs to fight poverty related and neglected parasitic diseases: synthetic and natural compounds directed against Leishmania, Plasmodium and Schistosoma life stages and assessment of their mechanisms of action

Malaria, leishmaniasis and schistosomiasis rank among the most devastating tropical diseases in the world. A core group of Italian scientists, with a long standing experience in Neglected Tropical Diseases and Poverty Related Diseases (NTDs and PRDs), decided to create the LeishPlaSch Consortium to bring their knowledge and their efforts together with the aim of achieving substantial advancements in the discovery of novel therapeutic and/or preventive drugs against Plasmodium, Leishmania and Schistosoma, the pathogens causing malaria (a PRD), leishmaniosis and schistosomiasis (PRDs and NTDs, respectively). There are three main arguments that constitute the rationale for the choice of the project’s target parasitic diseases: -All 3 parasites develops in the human host plus an invertebrate host/vector and all - at some stage of their life cycle - reproduce and/or mature in the blood of the human host; -There is evidence for multi-parasite activity of various drugs and molecules belonging to different chemical classes, e.g. artemisins exhibit activity on Plasmodium, Leishmania and Schistosoma; -The epidemiology and control of all 3 diseases is influenced by socioeconomic conditions, malnutrition, population mobility, environmental and climate changes. The goal of the proposal is to develop new, deployable products with targeted profiles against malaria, leishmaniasis and schistosomiasis, in particular by identifying new chemical entities appropriate for the pharmacological management of malaria, leishmaniasis and schistosomiasis. The goals of the LeishPlaSch consortium are: 1-Identification of disease specific and/or multi-antiparasitic new lead compounds, including repurposing approaches; 2-Identification of compounds with multistage effects for the development of combination treatments including transmission-blocking activity; 3-Validation of novel targets for drug discovery, including a structural biology approach; 4-Advancement of understanding parasite biology and drug-related host parasite relationships, including the definition of modes of action, and identification of new target pathways. LeishPlaSch Consortium will exploit the high scientific skills of Italian parasitologists, structural and molecular biologists, medicinal and natural organic chemists, biochemists, immunologists, and bioinformaticians. Most of the LeishPlaSch partners are active members of the Italian Malaria Network and already synergized their activities in EC funded projects such as FP6-AntiMal and BioMalPar, and FP7-EVIMalaR and InterMalTraining. The organization of the LeishPlaSch consortium is organized on 3 WPs, based on 3 main platforms: a Chemistry Platform, an Enzymatic and a Phenotypic in vitro platform and in vivo screening Platform. All three WPs will combine their interdisciplinary efforts to identify, select and investigate the mode of action of novel antiparasitic compounds.