Innovative Plasmodium G-quadruplexes ligands as new potential antimalarial drugs – MAG4

Our project aims at an original strategy to propose novel and innovative antimalarial drugs based on the design of small molecules that specifically target the G-quadruplexes structures present in the mitochondrial genome of Plasmodium falciparum.
Guanine-rich DNA and RNA sequences can fold into four-stranded non-canonical secondary structures called G-quadruplexes. The genome of malaria parasite, Plasmodium falciparum, is characterized by its extreme AT rich sequence (> 80 %). Given the A/T bias, only few regions of the parasite genome have the potential to form G4 structures. Nevertheless, the presence of G4 structures in Plasmodium has been confirmed by the use of a specific G4-detecting antibody. Interestingly, genome-wide analysis of nuclear and mitochondrial DNA of the Plasmodium parasite shows a higher G4 motif density in mitochondria in comparison to the nuclear DNA.
Our preliminary data, resulting from an active collaboration between partners 1 and 2 showed a very effective and selective activity of some acridine-based G-quadruplex (G4) ligands against Plasmodium falciparum. We tested 8 different G4 ligands and we demonstrated that RHPS4, a potent and selective G4 ligand, has a substantial antimalarial activity (IC50 = 75 nM) on multidrug resistant P. falciparum parasites strain. Moreover, we showed that RHPS4 exhibit a high selectivity for Plasmodium with respect to human cells with selectivity indexes (IC50 human cell/IC50 Plasmodium) ranging from 100 to more than 300. Strikingly, using a classical qPCR approach, we have also demonstrated that the treatment of P. falciparum with RHPS4 causes a drastic decrease of the mitochondrial DNA copy relative to global amount of Plasmodium genomic DNA.
From these data, the objective of this project is the research and development of RHPS4 derivatives as antimalarial-drugs acting through the stabilization of G-quadruplex structures present in the mitochondrial genome of Plasmodium falciparum.