New drug overcomes multiple resistance of malaria parasite – Third information

The parasite that causes malariaPlasmodium falciparummosquito-borneAnopheles, He is responsible for most of the cases in the world. Almost 96% of all malaria deaths in 2022 were attributed to the species, with the majority of cases occurring in sub-Saharan Africa where the disease is most common, according to the World Health Organization (WHO).

In 2018, the study was published in the journal Science have identified numerous mutations that allow P. falciparumbecomes resistant to the arsenal of treatments being developed.

Now a new job in Sciencepublished results and mechanism of action a new drug that overcomes some of these resistances. The experiment was carried out on a humanized mouse model developed at the GSK Global Health Research Center in Tres Cantos (Madrid).

Efficacy against resistant strains

The work was led by scientists from the California universities of Riverside and Irvine and the Yale School of Medicine (all in the USA). A medicine called MED6-189demonstrated effectiveness against strains P. falciparum sensitive and resistant to drugs like in vitro like mice modified to produce human blood.

As SINC explained Karine Le RocheProfessor of Molecular and Cellular Biology at the University of California, Riverside and lead author of the paper: “MED6-189 acts not only in the apicoplast, a specific organelle of cells P. falciparumbut also in vesicular movement pathways. This dual mechanism of action makes it difficult for parasites to develop multiple mutations in their genome to survive exposure to the drug.”

Le Roch adds that “interruption of apicoplast and vesicle movementg blocks the development of the parasite and therefore eliminates infection in red blood cells and in the humanized mouse model.” In addition, the team found that the drug was also effective against other zoonotic parasites. PlasmodiumHow P. knowlesi And P. cynomolgus“

New type of connection

The researcher points out that the human malaria parasite resistant to all antimalarial drugs current. Therefore, he emphasizes, “it is important to identify new classes of compounds that have not been used before and target new enzymes and molecular pathways.”

“MED6-189 is a very potent compound with IC50 (mean inhibitory concentration) values ​​similar to those of effective antimalarial drugs. It is also active against multiple drug-sensitive and drug-resistant strains of malaria,” he insists.

Spanish participation

Le Roch explains that it is not possible to test the compound’s activity against human malaria parasites using a standard mouse model (these animals are not infected with malaria parasites).P. falciparum): “Therefore, in the study, we used a humanized mouse model designed to human blood” This was done in collaboration with the team Javier GamoDirector of the GSK Global Health Research and Development Center in Tres Cantos.

Gameau detailed to SINC that in their work, researchers in his group genetically modified rodents so that “they were able to receive and stabilize transfusions of human red blood cells in their circulatory system and thus become humanized and become infected with the virus.” P. falciparumto determine effectiveness in natural conditions this antimalarial drug against a true parasite that infects humans“

Le Roch says the Tres Cantos group “has extensive experience with this type of model and was able to demonstrate significant activity of MED6-189 against the human malaria parasite.”

The team also tested the composition againstP. knowlesi, parasite that infects monkeys and found that it destroys red blood cells infected with this pathogen.

Extracted from sea sponges

The new antimalarial drug is a compound extracted from sea sponges. Laboratory Christopher VanderWaalprofessor of chemistry and pharmaceutical sciences at the University of California, Irvine, was responsible for its synthesis.

The main author of the work notes that natural products have advantages over synthetic molecules in drug discovery, as “they tend to be chemically novel and useful for treating complex metabolic targets.” And he gives examples of quinine and artemisinin, which are plant-derived and continue to be used against malaria.

As for sea sponges, he says that “they are a rich source of nnew biologically active compounds and serve as hosts for many microorganisms. They synthesize complex secondary metabolites with a wide range of biological activities.

As for next steps, Karine Le Roch says they are now conducting an investigation to obtain “important data on the absorption, distribution, metabolism and elimination of MED6-189 not only for improve dosage of e-cigarettesbut also the predictability of human pharmacokinetics.”

He insists the experimental drug is “extremely powerful due to its dual mechanism of action that prevents the pathogen from developing resistance, but the compound is complex.” Therefore, he adds, “we are also working to develop a cost-effective synthesis of MED6-189, which will help health systems treat malaria infections in developing countries“

Link:

Z. Sahin et al. “A caliquinol analog disrupts apicoplast function and vesicular transport in P. falciparum malaria.” Science (2024)