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Peer-reviewedCC BY 4.0Antimicrobial Agents and Chemotherapy

G-quadruplex-binding ligand RHPS4 reduces Plasmodium falciparum mitochondrial DNA level providing a novel antimalarial strategy

  • Mariam Salim1,2
  • Lucie Paloque1,2
  • Flore Nardella1,2
  • Thibaud Reyser1,2
  • Michel Nguyen1,2
  • Jean-Michel Augereau1,2
  • Yu Luo3,4
  • Sébastien Britton1
  • Jean-Louis Mergny3
  • Virginie Gervais5
  • Françoise Benoit-Vical1,2
  • Dennis Gomez1
5 affiliations
  1. 1IPBS, CNRS, Université de Toulouse, Toulouse, France
  2. 2Université de Toulouse, CNRS, Inserm, LCC, ERL 1289 MAAP, Toulouse, France
  3. 3Laboratoire d’Optique et Biosciences, Ecole Polytechnique, CNRS, Inserm, Institut Polytechnique de Paris, Palaiseau, France
  4. 4CNRS UMR9187, INSERM U1196, Institut Curie, PSL Research University, Orsay, France
  5. 5Université Paris-Saclay, CEA, CNRS - Institute for Integrative Biology of the Cell (I2BC), Gif-sur-Yvette, France
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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 drug-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 impacts P. falciparum mitochondrial DNA replication and transcription, leading to parasite death, and establish G4 ligands as novel antimalarial agents.

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Cite

BibTeXRIS
BibTeX
@article{salim2026gquadruplexbinding,
  title = {{G-quadruplex-binding ligand RHPS4 reduces Plasmodium falciparum mitochondrial DNA level providing a novel antimalarial strategy}},
  author = {Mariam Salim and Lucie Paloque and Flore Nardella and Thibaud Reyser and Michel Nguyen and Jean-Michel Augereau and Yu Luo and Sébastien Britton and Jean-Louis Mergny and Virginie Gervais and Françoise Benoit-Vical and Dennis Gomez},
  journal = {Antimicrobial Agents and Chemotherapy},
  year = {2026},
  month = oct,
  doi = {10.1128/aac.00144-26},
  url = {https://hal.science/hal-05802361v1},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - G-quadruplex-binding ligand RHPS4 reduces Plasmodium falciparum mitochondrial DNA level providing a novel antimalarial strategy
AU  - Mariam Salim
AU  - Lucie Paloque
AU  - Flore Nardella
AU  - Thibaud Reyser
AU  - Michel Nguyen
AU  - Jean-Michel Augereau
AU  - Yu Luo
AU  - Sébastien Britton
AU  - Jean-Louis Mergny
AU  - Virginie Gervais
AU  - Françoise Benoit-Vical
AU  - Dennis Gomez
PY  - 2026
DA  - 2026/10/01
JO  - Antimicrobial Agents and Chemotherapy
DO  - 10.1128/aac.00144-26
UR  - https://hal.science/hal-05802361v1
AB  - 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 drug-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 impacts P. falciparum mitochondrial DNA replication and transcription, leading to parasite death, and establish G4 ligands as novel antimalarial agents.
SN  - 0066-4804
SN  - 1098-6596
ER  -