In 2022, almost 619,000 deaths worldwide due to malaria were caused by Plasmodium falciparumthe most virulent, prevalent and deadly human malaria parasite. For decades, the parasite’s resistance to all antimalarial drugs has posed a major challenge to researchers working to stop the spread of the disease.
A team led by scientists from UC Riverside, UC Irvine and Yale School of Medicine has designed a new anti-malaria drug and identified its mechanism of action. Researchers found that the drug, called MED6-189, is effective against drug-sensitive and drug-resistant patients. P. falciparum strains in vitro, as well as in a humanized mouse model (the mice were designed to have human blood).
The researchers report in the journal. Science this week that MED6-189 works by targeting and altering not only the apicoplast, an organelle found in P. falciparum cells, but also vesicular trafficking pathways. They found that this dual mode of action prevents the pathogen from developing resistance, making the drug a highly effective antimalarial compound and a promising new lead in the fight against malaria.
“Disruption of apicoplast and vesicular trafficking blocks parasite development and therefore eliminates infection in red blood cells and in our humanized mouse model of P. falciparum malaria,” said Karine Le Roch, professor of molecular, cellular and systems biology at UCR and senior author of the paper. “We found that MED6-189 was also potent against other zoonotic Plasmodium parasites, such as P. knowlesi and P. cynomolgi.“
MED6-189 is a synthetic compound inspired by a compound extracted from marine sponges. The laboratory of Christopher Vanderwal, professor of chemistry and pharmaceutical sciences at UC Irvine, synthesized the compound.
“Many of the best antimalarial agents are natural products or derived from them,” he said. “For example, artemisinin, initially isolated from the sweet wormwood plant, and its analogs, are critically important for the treatment of malaria. MED6-189 is a close relative of a different class of natural products, called isocyanoterpenes, which appear to attack multiple pathways in P. falciparum. “This is beneficial because if only one pathway had been targeted, the parasite could develop resistance to the compound more quickly.”
When researchers at GSK, a Spanish pharmaceutical company, administered MED6-189 to mice infected with P. falciparumThey found that it eliminated the parasite from the mice. Collaborating with Choukri Ben Mamoun, professor of medicine and microbial pathogenesis at Yale School of Medicine, the team also tested the compound against P. knowlesia parasite that infects monkeys, and found that it worked as intended, eliminating parasite-infected red blood cells from the monkey.
Next, the team plans to continue optimizing MED6-189 and further confirm the mechanisms of action of the modified compound using a systems biology approach. Systems biology is a biomedical research approach to understanding the bigger picture of a biological system. It offers researchers a way to examine how different living organisms and cells interact at larger scales.
Le Roch, Vanderwal and Ben Mamoun were joined in the research by scientific colleagues at the Stowers Institute for Medical Research in Kansas City, Missouri; GSK; and the University of Georgia.
The research was funded by a grant to Le Roch, Vanderwal and Ben Mamoun and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health. At UCR, Le Roch directs the Center for Research on Infectious Diseases and Vectors.
The title of the research paper is “A potent Kalihinol analog alters apicoplast function and vesicular trafficking in P. falciparum Malaria.”