CE18 - Innovation biomédicale

Antileishmanial agents targeting host cell trafficking – LeishmaStop

Submission summary

Leishmaniases are a complex of tropical and sub-tropical diseases provoked by Leishmania protozoan parasites transmitted by the sandfly vector and presenting different clinical expressions. In 2018, about 12 million Humans are affected by leishmaniases but global climate warming and population movements increase spreading of the diseases. In South-European countries, L. infantum affects mainly 2.5 million dogs and sometimes humans. New canine cases are estimated at 40,000 a year in South of France whereas several hundreds of human cases occur annually in Southern Europe, mainly in children and immune-compromised patients.
The anti-leishmanial chemotherapy is expensive, aspecific therefore toxic, and drug resistance is usual or at risk, mainly to antimonials, the most classical drugs, and recently to miltefosine and amphotericin B. Despite the recent launching of CaniLeish, the first vaccine against canine leishmaniasis, new treatments are urgently needed because the vaccinal protection of dogs is expected to only reduce parasite loads in vivo and no vaccine is presently available for Human use. As a consequence, leishmaniasis is still poorly managed both in dogs and Humans. 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. Inhibitors of key elements of this diverted machinery should handicap the parasite survival.
We have identified inhibitors of the plant toxin ricin by molecular screening (Stechmann et al., Cell 2010). One molecule, called ABMA, efficiently protects cells against various toxins and pathogens including viruses, intracellular bacteria and parasite Leishmania infantum (Wu et al., Scientific reports 2017). As the mechanism of action of ABMA is restricted to host-endosomal compartments, it reduces cell infection by pathogens that depend on this pathway to invade cells. Thus, acting on the host cells and not on the pathogens, the molecule acts as cell protectant.
We screened over a hundred analogues of ABMA against L. infantum axenic and intra-macrophage amastigote forms of the parasite and observed various anti-parasitic activities. 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 an ABMA derivative in a mouse model of infection by intraperitoneal route reducing liver and spleen parasitic burden to 83% after a 5-day treatment. 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.

Project coordination

Julien Barbier (Institut des sciences du vivant FRÉDÉRIC-JOLIOT)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

JOLIOT Institut des sciences du vivant FRÉDÉRIC-JOLIOT
Drugabilis
BioCIS Université Paris-Sud, Chimiothérapie antiparasitaire, UMR 8076 CNRS BioCIS

Help of the ANR 529,626 euros
Beginning and duration of the scientific project: December 2018 - 36 Months

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