Selective Disruption of <i>Plasmodium falciparum</i> mitochondrial DNA via G-Quadruplex-Binding Ligand RHPS4 Provides a Novel Antimalarial Strategy
ABSTRACT Malaria caused by Plasmodium falciparum remains a major health threat, killing over 600,000 people annually. The spread of resistance to all major antimalarials, including artemisinins, highlights the urgent need for new drugs with distinct mechanisms of action. Here we show that the G-quadruplex ligand RHPS4, an acridine derivative, displays strong antiplasmodial activity against both drug-sensitive and -resistant P. falciparum strains and clinical isolates. RHPS4 primarily targets the trophozoite stage and induces major mitochondrial alterations, including reduction of mitochondrial DNA (mtDNA) and transcriptional dysfunctions. Bioinformatic analyses identified at least eight putative G4-forming sequences within the parasite’s mtDNA. Biophysical studies confirmed G4 folding of at least one sequence and its interaction with RHPS4. These findings indicate that RHPS4 disrupts P. falciparum mitochondrial metabolism through G4 stabilization, leading to parasite death, and establish mtDNA G4 structures as novel therapeutic targets for antimalarial development.
Authors
- Yu Luo (ORCID: https://orcid.org/0000-0002-7088-0715)
- Françoise Benoit‐Vical (ORCID: https://orcid.org/0000-0002-9468-4823)
- Jean‐Michel Augereau (ORCID: https://orcid.org/0000-0002-2847-1969)
- Doris Gomez (ORCID: https://orcid.org/0000-0002-9144-3426)
- Flore Nardella
- Thibaud Reyser
- Lucie Paloque (ORCID: https://orcid.org/0000-0003-0359-3959)
- Virginie Gervais (ORCID: https://orcid.org/0000-0002-1144-6185)
- Sébastien Britton
- Jean-Louis Mergny
- Mariam Salim
Institutions
- Centre National de la Recherche Scientifique (FR)
- Université Toulouse III - Paul Sabatier (FR)
- École Polytechnique (FR)
- Inserm (FR)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Université Paris Sciences et Lettres (FR)
- Université Paris-Saclay (FR)
- Institut de Pharmacologie et de Biologie Structurale (FR)
- Institut de Biologie Intégrative de la Cellule (FR)
- Laboratoire de Chimie de Coordination (FR)
- CEA Paris-Saclay (FR)
- Institut Curie (FR)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-01-07
- DOI
- https://doi.org/10.64898/2026.01.07.698092
- Primary Topic
- DNA and Nucleic Acid Chemistry
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Biogen
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Fondation pour la Recherche Médicale
- Medicines for Malaria Venture
- Centre National de la Recherche Scientifique
- Région Occitanie Pyrénées-Méditerranée