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ANR LeishmaStop

The team « Antiparasite chemotherapy » (Philippe Loiseau) of the BioCIS research unit is one partner of the LeishmaStop project, managed by Julien Barbier (CEA Saclay) and selected within the Collaborative Research Project (PRC) call of the ANR (2018). Leishmaniases are a complex of parasitic diseases provoked by Leishmania protozoan parasites transmitted by the sandfly vector and affecting Humans and animals. The anti-leishmanial chemotherapy is expensive, aspecific therefore toxic, and drug resistance is usual or at risk. New treatments are urgently needed based on a rational chemotherapy. Parasites such as Leishmania successfully strive in host cells because they divert the intracellular trafficking machinery to maintain their parasitophorous vacuole in which they proliferate. We have identified inhibitors efficiently protecting cells against Leishmania infantum. Lead compounds were selected based on selective activity against intramacrophage amastigote forms as well as favorable physicochemical properties. In vivo proof of concept was confirmed with a derivative in a mouse model of infection. Further analogue selection on drugability criteria led us to identify one potential drug candidate with one back-up analogue that have physicochemical properties compatible with production of an easy to produce, low cost, standard pill for oral administration for the treatment of leishmaniasis. The ultimate goal of the project is to develop of a new class of oral anti-leishmanial drug, targeting components of the host’s intracellular machinery instead of targeting the parasites therefore reducing the risk of drug resistance acquisition by the parasites. Our objectives are to raise lead compounds development to TRL4 : a drug candidate and its backup ready for regulatory safety studies and clinical evaluation in infected leishmaniasis dog patients. To this end, we shall achieve : (1) Scale-up synthesis in a scheme compatible with pharmaceutical production ; (2) In depth physicochemical characterization of best crystal forms ensuring stability, solubility after oral administration and formulation ; (3) Radiolabeling and biodistribution of the parent drug and metabolites in mice ; (4) Determination dose and duration of treatment, acute and chronic toxicity evaluation ; (5) Pharmacokinetics, metabolites and pre-regulatory tolerance in dogs ; (5) Full identification, synthesis and antiparasite activity evaluation of main metabolites identified in dogs ; (6) Deciphering mechanism of protection of cells from parasite growth.