R3

Antileishmanial agents targeting host cell trafficking

Coordinator: D. Gillet (Partner 11)
Starting date: January 2014

The goal of the RetroLeishma project, which involves 3 main partners (Partner 11, 12&15) is to evaluate and understand the basis for protection against Leishmania given by molecules of the Retro-1, Retro-2 and #20 series, which are inhibitors of intracellular trafficking. The study will be performed on Leishmaniainfantum, responsible for canine and also human leishmaniasis in the Mediterranean basin, including South Europe and France.

Leishmaniasis are a complex of tropical and sub-tropical diseases provoked by Leishmania protozoan parasites transmitted by the sandfly vector and presenting different clinical expressions. These diseases affect about 12 million humans and are in constant spreading. The antileishmanial chemotherapy is expensive, aspecific therefore toxic, and resistance is usual or at risk, mainly to antimonials, the most classical drugs, and to amphotericin B.

We found three molecules showing broad-spectrum protection of cells and/or mice against a series of bacterial toxins and infectious pathogens, including Leishmaniafor one of them. The three molecules named Retro-1, Retro-2 and #20 were identified in a high throughput screen against ricin in a cellular assay. Retro-1 and Retro-2 act by blocking toxin trafficking between the early endosome and the trans-Golgi network. #20 is suspected to block toxin transport from early endosomes to the late endosomes and lysosomes pathway. Retro-1 and Retro-2 induce redistribution of syntaxin (Syn)-5 and to a lesser degree, Syn-6 and Syn-16 from the Golgi apparatus to small compartments scattered in the cytoplasm. As host Syn-5 is involved in the maturation of Leishmania, a team at University of Florida found that Retro-2 limits experimental Leishmaniaamazonensis infections in the cell in vitro and in mice in vivo.