MaPI

Malaria is the most important human parasitic disease and a major public health concern. Since 2007, an ambitious goal of malaria elimination and eventually eradication has been set, control interventions have been scaled up and malaria cases have declined. Yet, there were still 220 million malaria cases in 2009. Innovative funding initiatives have been launched to subsidise drugs to the populations most at need. The market of antimalarials has been estimated at about 500 M€ for approx. 400 million treatments per year. Control now faces the threatening obstacle of drug parasite resistance, including resistance to recently introduced artemisinin-based combination therapies. To sustain control efficiency and to meet the challenge of elimination, new drugs are required. Development of novel antimalarials is long and expensive. Focus so far has been on a few drug targets of Plasmodium intraerythrocytic stages. This project aims at replenishing the drug pipeline with antimalarials active on new targets, expressed at different stages of both P.falciparum and P.vivax. The project builds on the validation by the Institut Pasteur (IP) team of novel promising drug targets, i.e. the SUB1 and SUB2 subtilisin proteases that orchestrate a cascade of events culminating in the egress of the parasite from and invasion into new host cells. Importantly, available evidence indicates that these subtilisins are essential in blood stages as well as in pre-erythrocytic stages. This R&D proposal will capitalise on recent drug discovery efforts by the IP team to execute in collaboration with Sanofi Aventis (SA) the translational research activities needed for the critical hit/early lead to lead generation. We will combine the expertise from the IP teams in parasitology, structural biology and epidemiology with the expertise of SA teams of Therapeutic Strategic Unit dedicated to Infectious diseases (TSU-ID), LG-CR (Lead Generation and Compound Realisation) and DSAR (Disposition Sécurité et Recherche Animale) to develop a new generation of anti-malarial lead compound qualified to enter into pre-clinical phases. The overall strategy will be to use iterative process of optimisation and testing of compounds targeting the Plasmodium SUBs proteases starting from the existing hits. The products will be evaluated for ADMET and for a set of biological activity criteria (inhibition of Pv/Pf/PbSUB1 recombinant enzymes, of SUB2 enzymes, of P.falciparum growth in vitro and P.berghei in vivo. Product design and optimisation will articulate medicinal chemistry with crystallographic and NMR structural studies, in silico docking, activity against the enzymes and inhibition assays on parasites, including multidrug-resistant field isolates of P.falciparum and P. vivax from Cambodia. The objective is to obtain a molecule fulfilling the specifications of being non-toxic, potent and soluble for further development of oral therapy against P.falciparum and P. vivax malaria. Three main approaches will be pursued: a) lead generation starting from the early lead CD3; b) validation of SUB1 inhibitor A11H6, and hit to lead development; c) a fragment-based approach (SA). The main emphasis will be on the CD3-based strategy, with the aim to increase CD3 anti-parasite potency by ten to twenty-fold and to increase its solubility, while the two alternate approaches will be explored as backup strategies in case CD3 fails to meet the desired product specification. The project has two main partners, an academic (IP) and an industrial (SA). Each partner will engage several teams and significant ressources. The objective of the project and its workplan is fully in line with the stated objectives of the call. We bridge the gap between academic, product-oriented research and industrial research to build upon and valorise the patented outcome of academic research and jointly execute a critical forward step towards development of new products needed by the market.