Scientists develop new drug to fight malaria

RIVERSIDE, California – In 2022, nearly 619,000 deaths worldwide were caused by malaria Plasmodium falciparumthe most virulent, widespread and deadly human malaria parasite. The parasite's resistance to all antimalarial drugs has been a major challenge for researchers working to stop the spread of the disease for decades.

A team led by scientists from UC Riverside, UC Irvine and the Yale School of Medicine has now developed a new anti-malaria drug and identified its mechanism of action. The researchers found that the drug, called MED6-189, is effective against both drug-sensitive and drug-resistant patients. P. falciparum strains in vitro and in a humanized mouse model (the mice were bred to receive human blood).

The researchers report in the journal Science this week that MED6-189 works by not only attacking and destroying the apicoplast, an organelle that is found in P. falciparum cells, but also the vesicular transport pathways. They found that this dual mechanism of action prevents the pathogen from developing resistance, making the drug a highly effective antimalarial drug and a promising new approach in the fight against malaria.

“Disruption of the apicoplast and vesicular transport blocks the development of the parasite and thus prevents 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 lead author of the study. “We found that MED6-189 is also effective against other zoonotic Plasmodium parasites, such as P. knowlesi And P. cynomolgi.”

MED6-189 is a synthetic compound inspired by a compound extracted from sea sponges. The laboratory of Christopher Vanderwal, professor of chemistry and pharmacy at UC Irvine, synthesized the compound.

“Many of the best antimalarials are natural products or are derived from them,” he said. “For example, artemisinin, originally isolated from the annual wormwood plant, and analogues of it are critical for the treatment of malaria. MED6-189 is a close relative of another class of natural products, the isocyanoterpenes, which appear to have multiple pathways in P. falciparum. This is an advantage because if only one signaling pathway were attacked, the parasite could develop resistance to the compound more quickly.”

When researchers at the Spanish pharmaceutical company GSK discovered P. falciparumthey found that it cleared the mice of the parasite. In collaboration with Choukri Ben Mamoun, Professor of Medicine and Microbial Pathogenesis at the 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 the monkeys' red blood cells infected by the parasite.

Next, the team plans to continue optimizing MED6-189 and further confirm the modified compound's mechanisms of action using a systems biology approach. Systems biology is a biomedical research approach to understanding the big picture of a biological system. It provides researchers with a way to study how different living things and cells interact on a larger scale.

Le Roch, Vanderwal and Ben Mamoun were supported in their research by colleagues at the Stowers Institute for Medical Research in Kansas City, Missouri, GSK and the University of Georgia.

The research was supported 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 Infectious Diseases and Vector Research.

The title of the research paper is “A potent kalihinol analogue disrupts apicoplast function and vesicular transport in P. falciparum Malaria.”

The University of California, Riverside is a doctoral research university, a living laboratory for groundbreaking research on issues of critical importance to inland Southern California, the state and communities around the world. Reflecting California's diverse culture, UCR has an enrollment of more than 26,000 students. The campus opened a medical school in 2013 and has reached into the heart of the Coachella Valley through the UCR Palm Desert Center. The campus has an annual impact of more than $2.7 billion on the U.S. economy. For more information, visit www.ucr.edu.