Epidrugs as Promising Tools to Eliminate Plasmodium falciparum Artemisinin-Resistant and Quiescent Parasites.

Autor: Reyser T; LCC-CNRS, Laboratoire de Chimie de Coordination, Université de Toulouse, CNRS, 31077 Toulouse, France.; MAAP, New Antimalarial Molecules and Pharmacological Approaches, Inserm ERL 1289, 31077 Toulouse, France.; Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, Université Toulouse III-Paul Sabatier (UPS), 31077 Toulouse, France., Paloque L; LCC-CNRS, Laboratoire de Chimie de Coordination, Université de Toulouse, CNRS, 31077 Toulouse, France.; MAAP, New Antimalarial Molecules and Pharmacological Approaches, Inserm ERL 1289, 31077 Toulouse, France.; Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, Université Toulouse III-Paul Sabatier (UPS), 31077 Toulouse, France., Nguyen M; LCC-CNRS, Laboratoire de Chimie de Coordination, Université de Toulouse, CNRS, 31077 Toulouse, France.; MAAP, New Antimalarial Molecules and Pharmacological Approaches, Inserm ERL 1289, 31077 Toulouse, France.; Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, Université Toulouse III-Paul Sabatier (UPS), 31077 Toulouse, France., Augereau JM; LCC-CNRS, Laboratoire de Chimie de Coordination, Université de Toulouse, CNRS, 31077 Toulouse, France.; MAAP, New Antimalarial Molecules and Pharmacological Approaches, Inserm ERL 1289, 31077 Toulouse, France.; Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, Université Toulouse III-Paul Sabatier (UPS), 31077 Toulouse, France., Fuchter MJ; Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, White City Campus, London W12 0BZ, UK., Lopez M; Institut des Biomolécules Max Mousseron (IBMM), CNRS, Université de Montpellier, ENSCM UMR 5247, 34293 Montpellier, France., Arimondo PB; Epigenetic Chemical Biology, Department of Structural Biology and Chemistry, Institut Pasteur, Université de Paris-Cité, UMR 3523 CNRS, 75015 Paris, France., Hassell-Hart S; Department of Chemistry, School of Life Sciences, University of Sussex, Falmer BN1 9QJ, UK., Spencer J; Department of Chemistry, School of Life Sciences, University of Sussex, Falmer BN1 9QJ, UK., Di Stefano L; MCD, Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, 31062 Toulouse, France., Benoit-Vical F; LCC-CNRS, Laboratoire de Chimie de Coordination, Université de Toulouse, CNRS, 31077 Toulouse, France.; MAAP, New Antimalarial Molecules and Pharmacological Approaches, Inserm ERL 1289, 31077 Toulouse, France.; Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, Université Toulouse III-Paul Sabatier (UPS), 31077 Toulouse, France.
Jazyk: angličtina
Zdroj: Pharmaceutics [Pharmaceutics] 2023 Oct 10; Vol. 15 (10). Date of Electronic Publication: 2023 Oct 10.
DOI: 10.3390/pharmaceutics15102440
Abstrakt: The use of artemisinin and its derivatives has helped reduce the burden of malaria caused by Plasmodium falciparum. However, artemisinin-resistant parasites are able, in the presence of artemisinins, to stop their cell cycles. This quiescent state can alter the activity of artemisinin partner drugs leading to a secondary drug resistance and thus threatens malaria eradication strategies. Drugs targeting epigenetic mechanisms (namely epidrugs) are emerging as potential antimalarial drugs. Here, we set out to evaluate a selection of various epidrugs for their activity against quiescent parasites, to explore the possibility of using these compounds to counter artemisinin resistance. The 32 chosen epidrugs were first screened for their antiplasmodial activity and selectivity. We then demonstrated, thanks to the specific Quiescent-stage Survival Assay, that four epidrugs targeting both histone methylation or deacetylation as well as DNA methylation decrease the ability of artemisinin-resistant parasites to recover after artemisinin exposure. In the quest for novel antiplasmodial drugs with new modes of action, these results reinforce the therapeutic potential of epidrugs as antiplasmodial drugs especially in the context of artemisinin resistance.
Databáze: MEDLINE
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