DNA Methylation Bisubstrate Inhibitors Are Fast-Acting Drugs Active against Artemisinin-Resistant Plasmodium falciparum Parasites

Autor: Salah Mecheri, Benoit Witkowski, Flore Nardella, Artur Scherf, Elie Hammam, Ludovic Halby, Roger Peronet, Didier Menard, Véronique Cadet-Daniel, Diane Erdmann, Paola B. Arimondo
Přispěvatelé: Biologie des Interactions Hôte-Parasite - Biology of Host-Parasite Interactions, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Chimie biologique épigénétique - Epigenetic Chemical Biology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), ED 515 - Complexité du vivant, Sorbonne Université (SU), Malaria Molecular Epidemiology, Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), This work was supported by a European Research Council Advanced Grant (PlasmoSilencing 670301), a Fondation Pasteur Swiss grant and the French Parasitology consortium ParaFrap (ANR-11-LABX0024) to A.S., as well as DARRI Carnot Pasteur MS 2019 Projet INNOV-5-19 to A.S. and P.B.A., DIM1 Health Ile de France 2019 to P.B.A., and PTR Institut Pasteur 2019 (TaME) to L.H. and F.N, We thank Dr. T. Ishino (Department of Medical Zoology, Mie University School of Medicine, Edobashi, Tsu, Japan) for her kind gift of the P. berghei ANKA GFP-expressing strain.(26) We thank Agnès Zettor and Fabrice Agou of the PF-CCB (Institut Pasteur) for the solubility analysis and Eric Legrand (Biology of Host-Parasite Interactions, Institut Pasteur, Paris) for his technical assistance., ANR-11-LABX-0024/11-LABX-0024,ParaFrap,Alliance française contre les maladies parasitaires(2011), European Project: 670301,H2020,ERC-2014-ADG,PlasmoSilencing(2015), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Chimie biologique épigénétique - Epigenetic Chemical Biology (EpiCBio), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Ecole Doctorale Complexité du Vivant (ED515), Université Paris Cité (UPCité), Réseau International des Instituts Pasteur (RIIP), ANR-11-LABX-0024,ParaFrap,Alliance française contre les maladies parasitaires(2011), MECHERI, Salah, Laboratoires d'excellence - Alliance française contre les maladies parasitaires - - ParaFrap2011 - ANR-11-LABX-0024 - LABX - VALID, Exoribonuclease-mediated degradation of nascent RNA in Malaria Parasites: A Novel Mechanism in Virulence Gene Silencing - PlasmoSilencing - - H20202015-11-01 - 2020-10-31 - 670301 - VALID, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université de Paris (UP)
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Artemisinins
General Chemical Engineering
[CHIM.THER]Chemical Sciences/Medicinal Chemistry
010402 general chemistry
01 natural sciences
Plasmodium
[SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity
[SDV.IMM.VAC] Life Sciences [q-bio]/Immunology/Vaccinology
In vivo
parasitic diseases
medicine
[CHIM]Chemical Sciences
[SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology
Artemisinin
[SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology
[SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity
QD1-999
biology
010405 organic chemistry
Plasmodium falciparum
General Chemistry
medicine.disease
biology.organism_classification
Virology
0104 chemical sciences
3. Good health
Chemistry
[SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology
[SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology
Parasitic disease
DNA methylation
[SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology
[SDV.IMM.ALL] Life Sciences [q-bio]/Immunology/Allergology
[SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology
Malaria
Research Article
medicine.drug
Zdroj: ACS Central Science
ACS Central Science, ACS Publications, In press, ⟨10.1021/acscentsci.9b00874⟩
ACS Central Science, 2020, 6 (1), pp.16-21. ⟨10.1021/acscentsci.9b00874⟩
ACS Central Science, Vol 6, Iss 1, Pp 16-21 (2019)
ACS Central Science, ACS Publications, 2020, 6 (1), pp.16-21. ⟨10.1021/acscentsci.9b00874⟩
ISSN: 2374-7951
DOI: 10.1021/acscentsci.9b00874⟩
Popis: Malaria is the deadliest parasitic disease affecting over 200 million people worldwide. The increasing number of treatment failures due to multi-drug-resistant parasites in South-East Asia hinders the efforts for elimination. It is thus urgent to develop new antimalarials to contain these resistant parasites. Based on a previous report showing the presence of DNA methylation in Plasmodium, we generated new types of DNA methylation inhibitors against malaria parasites. The quinoline–quinazoline-based inhibitors kill parasites, including artemisinin-resistant field isolates adapted to culture, in the low nanomolar range. The compounds target all stages of the asexual cycle, including early rings, during a 6 h treatment period; they reduce DNA methylation in the parasite and show in vivo activity at 10 mg/kg. These potent inhibitors are a new starting point to develop fast-acting antimalarials that could be used in combination with artemisinins.
Bisubstrate inhibitors of DNA methylation efficiently kill malaria parasites, including artemisinin-resistant ones. They act in 6 h during all stages of the asexual cycle and show in vivo activity.
Databáze: OpenAIRE
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