RedoxCURE-TPDs

Malaria is the most devastating parasitic disease for humans, with more than 200 million cases and 450,000 deaths per year. The efficiency of artemisinin-based combination therapy, the spearhead of malarial treatment is now threatened by the development of drug resistant parasites displaying enhanced transmission potential to mosquitoes. The development of parasite transmission blockers is a priority defined by the WHO. Chagas disease (CD) and schistosomiasis (SCH) are tropical parasitic diseases (NTDs) that are considered as the greatest missed opportunities atop the priorities for WHO. CD is caused by the protozoan Trypanosoma cruzi. It is endemic in Latin America and spreads around the globe due to human migration through multiple transmission routes, from vectorial, congenital, oral to iatrogenic. Today, 8 million people worldwide are infected and CD remains the main cause of death due to heart failure in Latin America and of infectious cardiomyopathy in the world. Female genital SCH is one of the most common gynecologic conditions of women who live in poverty in Africa and has emerged as one of the most important cofactors in AIDS epidemic there. There is still a significant gap in the anti-CD& -SCH drug discovery landscape. The coordinator team has pioneered redox chemistry and molecular understanding of the 3-benzylmenadione (benzylMD) scaffold selected as a chemotype with cross-pathogen activity. By screening a home-made library of benzylMDs, 3 compounds were selected with potent and specific activities to kill malaria parasites, T. cruzi parasites, or adult schistosomal worms. These redox-active agents kill parasites by a combination of redox-mediated mechanisms and direct target inhibition that remain poorly characterized in living parasites. Plasmodione is a new early lead benzylmenadione derivative identified by the Coordinator, displaying fast-acting antimalarial activity and potential transmission-blocking properties, without signs of toxicity even in G6PD-deficient red blood cells, a condition increasing intracellular oxidative stress in Africa. A new plasmodione derivative, MD040, was recently selected for improved pharmacokinetics, potent activity against mature gametocytes (P. falciparum), high transmission-blocking properties in vivo (P. berghei-infected mouse to Anopheles gambiae mosquitoes). Recent investigation in the yeast model revealed mitochondrial flavoenzymes involved in electron transfers as possible targets for plasmodione. Cruzidione is a confirmed lead compound with validated anti-CD activity in vitro and in vivo. The compound was checked for sterile cidality of intra-macrophagic amastigotes in the assay advocating for no relapse of amastigotes after drug-washout. Schistodiones are two regioisomers killing adult Schistosoma mansoni worms ex vivo and active in vivo in mice. The compounds induce striking phenotypic effects, called hairy phenotype, suggesting a significant perturbation of metabolic pathways. In the RedoxCURE-NTDs project, a network of complementary expertise will be set-up based on a multidisciplinary approach combining organic chemistry, physico(bio)chemistry, proteomics, genetics, biochemistry, chemoinformatics, and parasitology. Our consortium RedoxCURE-NTDs wish to propose a PhD-Training Network based on 12 highly complementary and interdisciplinary renowned teams from 3 EU countries, 2 associated countries, and 2 disease-endemic countries. The main goals of this network are (1) to take our lead compounds to preclinical development, (2) to transfer the knowledge and excellence of respective methodologies to PhD students and to endemic countries. To fill the gap in drug discovery towards the treatment of NTDs and to prepare the PhD students for positions in academic research or in pharmaceutical industries, a public-private consortium will be established with the goal of delivering three drug candidates to treat Malaria, CD and SCH.