Resistance to malaria is a global health issue that researchers must continually address in the fight against Plasmodium parasites. This virus has already been transmitted to people worldwide through bites from infected mosquitoes. The incidence also increases from year to year as resistance to malaria and its treatment steadily increases.
Increase resistance to malaria
The parasites are usually able to adapt to different environments. Scientists at the Institut Pasteur and the Center National de la Recherche Scientifique (CNRS) have discovered new types of DNA methylationInhibitors against the parasite of malaria infectionsdeveloped. Thus, the quinoline-quinazoline-based inhibitors kill the parasites, including artemisinin-resistant field isolates adapted to culture, at low nanomolar levels.
The compounds target all stages of the asexual cycle, including the early rings, during a 6-hour treatment period. They reduce DNA methylation in the parasite and show activity at 10 mg/kg. These effective inhibitors represent a completely new starting point for the development of fast-acting agents for resistance to malaria, which could be used in combination with artemisinins.
“In each phase of the cycle, epigenetic mechanisms such as histone or DNA modifications regulate the expression of the parasite genes, allowing the specific expression of some genes in the cell at a given time, allowing the parasite to adapt to its environment,” explains Flore Nardella . He is a researcher in the Laboratory of Biology of Host-Parasite Interactions at the Pasteur Institute.
New research results
In 2019, the laboratory demonstrated the importance of epigenetic DNA modifications for the parasite's life cycle. The Epigenetic Chemical Biology Laboratory at the Institut Pasteur also has unparalleled expertise in the field of DNA methylation of inhibitors. For this reason, it was only logical that the two teams work together to identify molecules that can inhibit the process and kill parasites.
Scientists decided to work on this, specifically studying strains of artemisinin-resistant parasites. In the first series of test tube experiments, the parasites were allowed to interact with human red blood cells. This allowed them to become infected and develop. The researchers then tested more than 70 methylation-inhibiting molecules for their effectiveness and specificity in relation to the parasites.
In the third phase of the research, the scientific team tested the inhibitors on laboratory mice. These were infected with the Plasmodium parasite. The approach once again proved successful. The treatment killed the blood parasites and the mice survived the cerebral infection thanks to resistance to malaria. The next steps for the two research teams are to further optimize the selectivity and effectiveness of the most promising molecules. This allows them to identify molecules that may affect other developmental stages of the parasite responsible for transmission.
The results of the research were published in the journalACS Central Sciencepublished.
