Malaria (MAL) and schistosomiasis (SCH) are infectious diseases of poverty of global importance. No vaccines are available and new chemotypes are urgently needed for the development of drugs to fight those two diseases. For MAL, caused by Plasmodium spp. parasites and transmitted by Anopheles spp. mosquitoes, the problem is the spread of resistance to the currently available drugs, including artemisinin-based therapies. Female genital SCH caused by Schistosoma spp, is one of the most common gynecologic conditions of women who live in poverty in Africa and has emerged as one of Africa's most important cofactors in its AIDS epidemic. For SCH, only one drug, praziquantel, is available; but resistant parasites jeopardize the efficacy of cure rates at high infection intensities. To overcome these gaps, we have established a French-Swiss academic consortium, ROSaction with complementary expertise, which includes chemistry, parasitology and yeast genetics, with the aim of developing preclinical candidates of the 3-benzylmenadione (bMD) series: plasmodione (against MAL) and schistodiones (against SCH). Depending on their chemical substitution pattern, bMDs have highly specific and potent antiparasitic activities on Plasmodium spp., or Schistosoma mansoni worms, both in vitro and in vivo, with no obvious signs of toxicity in mice and in G6PD-deficient red blood cells. The goal of this application is to optimize the discovered early bMD-based leads for each disease model, to improve their pharmacokinetic properties, to validate the respective antiparasitic properties of the optimized compounds in vivo, and to identify the sensitive parasite stages, the drug modes of action and their protein targets. Mode of action studies conducted by the French teams with P. falciparum and Saccharomyces cerevisiae have indicated that the bMD derivatives are substrates of mitochondrial NADH-dehydrogenases, and that the chemical reduction of the bMD derivatives initiates a redox cycling process that results in the production of reactive oxygen species (ROS). The Swiss applicants of the project have established a strong expertise in antiparasitic drug efficacy testing. They have developed various in vitro and in vivo models for Plasmodium and S. mansoni, which are being used in hit discovery and hit-to-lead development of new antiparasitic agents. The proposed research program is divided into three work packages (WP). In WP1, we will synthesize novel 3-benzylmenadione analogues of plasmodione and schistodiones with improved antiparasitic activitiy, selectivity, and pharmacokinetics, and a second generation of activity-based protein profiling (ABPP) probes based on the 3-bMD scaffold. In WP2, the antiparasitic properties and selectivity profile of the molecules synthesized in WP1 will be assessed on P. falciparum and S. mansoni. The results will guide further optimization of the compounds (WP1) and enable mechanistic studies that will be performed in WP3. In WP3, we will investigate the mode of action of the antimalarial plasmodione and search for drug targets and possible mechanism of resistance. Using high throughput approaches in the yeast model, we will identify new targets by extending our screens for PD-resistant and hypersensitive yeast mutants. In parallel, activity-based protein profiling (ABPP) probes (synthesized in WP1) will enable us to capture and identify plasmodione targets in P. falciparum. Candidate drug targets and resistance genes/mutations will be validated in the parasite by genetic constructions. We will study the mode of action of schistodiones using yeast as a model and on the basis of the knowledge acquired in Plasmodium. We aim at providing a molecular understanding on how bMDs kill parasites and what is the basis of their selectivity.

During the past 50 years, arboviral (arthropode-borne viral) diseases, including dengue, Zika, chikungunya and yellow fever, have (re-)emerged. The arboviruses are transmitted primarily by the tropical yellow fever mosquito, Aedes aegypti, and to a lesser extent by Ae. albopictus, the Asian tiger mosquito, capable of colonizing both tropical and temperate regions. Dengue virus is on the rise, causing about 390 million human infections per year, chikungunya virus spread worldwide in the early 2000s, Zika virus spread worldwide in the past 3 years, and yellow fever has resurged in Africa and the Americas. The expansion of these diseases can be explained in part by an intensification of the conditions favoring the dispersal and proliferation of Aedes as a result of global trade and unplanned urbanization, a lack of community engagement and political will, and inefficient implementation of vector control programs. Although a vaccine is available for yellow fever, it is not accessible to many living in disease-endemic areas and the recenty developed dengue vaccine, Dengvaxia® shows limited efficacy and safety concerns. In this context, preventing Aedes-Borne Diseases (ABDs) at a global scale continues to depend largely on controlling mosquito vector populations or interrupting human–vector contact. Unfortunately, control of mosquitoes using larval source management and public health insecticides is fraught with complications, including slow operational response, low community buy-in, ineffective timing of application and occurrence of insecticide resistance. A recent systematic review highlights that 57 countries (including Italy, Greece and Spain) reported resistance (or suspected resistance) to at least one chemical class of insecticides in Ae. aegypti or Ae. albopictus. Insecticide resistance is recognized as a major threat for the control of ABDs and has likely contributed to their re-emergence and spread worldwide. Unlike malaria vectors, the evidence-base to support Insecticide Resistance Management (IRM) in arbovirus vectors is weak which make prioritization for vector control difficult. In addition, important knowledge gaps remain for Aedes resistance including its distribution, evolution, mechanisms, fitness costs and its impact on vector control efficacy. Finally, most countries lack of capacity in monitoring insecticides resistance that is essential for guiding pesticide management systems on appropriate use and reduction of risks to human health and environment. A global, coordinated, multi-disciplinary and cross-sectoral approach is needed to track insecticide resistance in vectors of emerging arboviruses and to guide the deployment of resistance breaking strategies. Such coordinated effort fits well with the MSCA-RISE-2020 call that promotes collaborative research and innovation activities between public and private organizations throughout the world. The WIN-RISE will improve the surveillance of insecticide resistance worldwide, fill knowledge gaps and guide decision making for improved IRM strategies and vector control in countries at risk of arbovirus transmission. It will develop comprehensive guidance on how and when to implement IRM to preserve the “susceptibility” of new/existing insecticides. The inclusion of all actors involved in vector control, pesticide development and regulation is key for success. The consortium will offer an attractive platform for stimulating the development of innovative vector control tools by fostering public-private partnerships. These actions will contribute to strengthen the vector research and training capacities of institutions located in low and middle-income countries, and to raise public awareness on vector resistance and control. The ultimate goal of the WIN-RISE is to sustain global efforts to reduce the burden of Neglected Tropical Diseases by 2030 (SDG3.3).