3-Benzylmenadiones and their Heteroaromatic Analogues Target the Apicoplast of Apicomplexa Parasites: Synthesis and Bioimaging Studies
Year: 2024
Type: article
Abstract: The apicoplast is an essential organelle for the viability of apicomplexan parasites Plasmodium falciparum or Toxoplasma gondii, which has been proposed as a suitable drug target for the development of new antiplasmodial drug-candidates. Plasmodione, an antimalarial redox-active lead drug is active at low nM concentrations on several blood stages of Plasmodium such as early rings and gametocytes. Nevertheless, its precise biological targets remain unknown. Here, we described the synthesis and the evaluation of new heteroaromatic analogues of plasmodione, active on asexual blood P. falciparum stages and T. gondii tachyzoites. Using a bioimaging-based analysis, we followed the morphological alterations of T. gondii tachyzoites and revealed a specific loss of the apicoplast upon drug treatment. Lipidomic and fluxomic analyses determined that drug treatment severely impacts apicoplast-hosted FASII activity in T. gondii tachyzoites, further supporting that the apicoplast is a primary target of plasmodione analogues. To follow the drug localization, “clickable” analogues of plasmodione were designed as tools for fluorescence imaging through a Cu(I)-catalyzed azide–alkyne cycloaddition reaction. Short-time incubation of two probes with P. falciparum trophozoites and T. gondii tachyzoites showed that the clicked products localize within, or in the vicinity of, the apicoplast of both Apicomplexa parasites. In P. falciparum, the fluorescence signal was also associated with the mitochondrion, suggesting that bioactivation and activity of plasmodione and related analogues are potentially associated with these two organelles in malaria parasites.
Source: ACS Infectious Diseases
Institutions: Centre National de la Recherche Scientifique, Laboratoire d'innovation moléculaire et applications, Inserm, Institut pour l'avancée des biosciences, Université Grenoble Alpes, Modèles Insectes de l'Immunité Innée, Institut de Biologie Moléculaire et Cellulaire, Université de Strasbourg, Rheinland-Pfälzische Technische Universität Kaiserslautern-Landau, Université de Montpellier, Laboratory of Pathogens and Host Immunity, Swiss Tropical and Public Health Institute, University of Basel
Language: English
Topic: Malaria Research and Control
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Université Grenoble Alpes, Communauté Université Grenoble Alpes, Alliance Française contre les Maladies Parasitaires, Agence Nationale de la Recherche, Indo-French Centre for the Promotion of Advanced Research, Fondation pour la Recherche Médicale, Centre National de la Recherche Scientifique, Région Auvergne-Rhône-Alpes, Europäische Konföderation der Oberrheinischen Universitäten
Awards: G2331484096, Elucidating the metabolic and lipidic adaptation of Toxoplasma gondii towards its human host nutritional environment, G311957854, Understanding how lipid trafficking at membrane contact sites allows the survival and propagation of Toxoplasma gondii within its human host, Deciphering the mechanisms of action of two antimalarial redox-active drugs with gametocytocidal and transmission-blocking properties - from yeast to malarial parasites, Redox-active benzylmenadiones against malaria and Schistosoma parasites, Alliance française contre les maladies parasitaires, G8486087644
OpenAlex ID: W4402929627