%0 Journal Article %T Hemisynthetic alkaloids derived from trilobine are antimalarials with sustained activity in multidrug-resistant Plasmodium falciparum %+ Biologie des Interactions Hôte-Parasite - Biology of Host-Parasite Interactions %+ Chimie biologique épigénétique - Epigenetic Chemical Biology (EpiCBio) %+ Centre de Production et Infection des Anophèles (plateforme) - Center for the Production and Infection of Anopheles (platform) (CEPIA) %+ Pharmacochimie de la Régulation Epigénétique du Cancer (ETaC) %+ Plateforme de Protéomique / Proteomics platform %+ Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM) %+ Institut Pasteur du Cambodge %A Nardella, Flore %A Dobrescu, Irina %A Hassan, Haitham %A Rodrigues, Fabien %A Thiberge, Sabine %A Mancio-Silva, Liliana %A Tafit, Ambre %A Jallet, Corinne %A Cadet-Daniel, Véronique %A Goussin, Stéphane %A Lorthiois, Audrey %A Menon, Yoann %A Molinier, Nicolas %A Pechalrieu, Dany %A Long, Christophe %A Sautel, François %A Matondo, Mariette %A Duchateau, Magalie %A Médard, Guillaume %A Witkowski, Benoit %A Scherf, Artur %A Halby, Ludovic %A Arimondo, Paola, B %Z This work was supported by Institut Pasteur-Institut Carnot (S-CR18089-02B15 DARRI CONSO INNOV 46-19; S-PI15006-10A INNOV 05-2019 ARIMONDO IARP 2019-PC), Pasteur Transversal Research Program (PTR 233-2019 HALBY), Pasteur Swiss Foundation grant, Agence Nationale de la Recherche (ANR-20-CE18-0006 EpiKillMal), Pasteur-Roux-Cantarini Fellowship and French Parasitology consortium ParaFrap, Grant (ANR-11-LABX0024). %< avec comité de lecture %J iScience %I Elsevier %V 26 %N 2 %P 105940 %8 2023-02 %D 2023 %R 10.1016/j.isci.2023.105940 %M 36718363 %Z Life Sciences [q-bio]/Human health and pathology %Z Chemical Sciences/Analytical chemistryJournal articles %X Malaria eradication requires the development of new drugs to combat drug-resistant parasites. We identified bisbenzylisoquinoline alkaloids isolated from Cocculus hirsutus that are active against Plasmodium falciparum blood stages. Synthesis of a library of 94 hemi-synthetic derivatives allowed to identify compound 84 that kills multi-drug resistant clinical isolates in the nanomolar range (median IC50 ranging from 35 to 88 nM). Chemical optimization led to compound 125 with significantly improved preclinical properties. 125 delays the onset of parasitemia in Plasmodium berghei infected mice and inhibits P. falciparum transmission stages in vitro (culture assays), and in vivo using membrane feeding assay in the Anopheles stephensi vector. Compound 125 also impairs P. falciparum development in sporozoite-infected hepatocytes, in the low micromolar range. Finally, by chemical pull-down strategy, we characterized the parasite interactome with trilobine derivatives, identifying protein partners belonging to metabolic pathways that are not targeted by the actual antimalarial drugs or implicated in drug-resistance mechanisms. %G English %Z We thank Bertrand Raynal of the Plateforme de Biophysique Moléculaire, in C2RT Pasteur Institute, for technical help. We thank the Center for Production and Infection of Anopheles (CEPIA) in Institut Pasteur for the mosquito breeding and handling. We thank Bruno Vitorge and Remy Lemeur from the Institut Pasteur Biological NMR Technological Plat-form for assisting with NMR experiments, Frédéric Bonhomme of the CNRS-Institut Pasteur UMR3523 Organic Chemistry Unit for performing HRMS analysis. %2 https://pasteur.hal.science/pasteur-04099097/document %2 https://pasteur.hal.science/pasteur-04099097/file/main.pdf %L pasteur-04099097 %U https://pasteur.hal.science/pasteur-04099097 %~ PASTEUR %~ RIIP %~ CNRS %~ RIIP_CAMBODGE %~ INC-CNRS %~ UNIV-PARIS %~ UNIVERSITE-PARIS %~ ANR