Hemisynthetic alkaloids derived from trilobine are antimalarials with sustained activity in multidrug-resistant Plasmodium falciparum

Autor: Flore Nardella, Irina Dobrescu, Haitham Hassan, Fabien Rodrigues, Sabine Thiberge, Liliana Mancio-Silva, Ambre Tafit, Corinne Jallet, Véronique Cadet-Daniel, Stéphane Goussin, Audrey Lorthiois, Yoann Menon, Nicolas Molinier, Dany Pechalrieu, Christophe Long, François Sautel, Mariette Matondo, Magalie Duchateau, Guillaume Médard, Benoit Witkowski, Artur Scherf, Ludovic Halby, Paola B. Arimondo
Přispěvatelé: Biologie des Interactions Hôte-Parasite - Biology of Host-Parasite Interactions, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Chimie biologique épigénétique - Epigenetic Chemical Biology (EpiCBio), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre de Production et Infection des Anophèles (plateforme) - Center for the Production and Infection of Anopheles (platform) (CEPIA), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Pharmacochimie de la Régulation Epigénétique du Cancer (ETaC), PIERRE FABRE-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Plateforme de Protéomique / Proteomics platform, Université Paris Cité (UPCité)-Spectrométrie de Masse pour la Biologie – Mass Spectrometry for Biology (UTechS MSBio), Institut Pasteur [Paris] (IP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut Pasteur [Paris] (IP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP), 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)., 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., ANR-20-CE18-0006,EpiKillMal,Cibler la méthylation de l'ADN pour contrer la chimiorésistance du paludisme(2020), ANR-11-LABX-0024,ParaFrap,Alliance française contre les maladies parasitaires(2011)
Rok vydání: 2023
Předmět:
Zdroj: iScience
iScience, 2023, 26 (2), pp.105940. ⟨10.1016/j.isci.2023.105940⟩
ISSN: 2589-0042
DOI: 10.1016/j.isci.2023.105940
Popis: International audience; 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.
Databáze: OpenAIRE
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