A new drug targeting malaria has been developed by a collaborative team of researchers who have also understood how it functions.
In 2022, malaria was responsible for nearly 619,000 deaths worldwide, predominantly attributed to Plasmodium falciparum, the most aggressive and deadly malaria parasite affecting humans. For many years, the parasite’s ability to resist all existing antimalarial treatments has posed a significant hurdle for scientists striving to control the disease’s spread.
Scientists from UC Riverside, UC Irvine, and Yale School of Medicine have come together to create a new malaria drug and unveil its mechanisms. Their findings indicate that the drug, named MED6-189, shows effectiveness against both drug-sensitive and drug-resistant strains of P. falciparum, tested in laboratory conditions and in humanized mice (mice designed to mimic human blood conditions).
In a recent publication in the journal Science, the researchers described how MED6-189 functions by targeting and disrupting the apicoplast, an organelle specific to P. falciparum, alongside disrupting vesicular trafficking pathways. This unique dual-action approach hinders the parasite from developing drug resistance, establishing MED6-189 as a potent antimalarial agent and a promising candidate in combating malaria.
“By disrupting the apicoplast and vesicular trafficking, we hinder the development of the parasite, which eliminates the infection in red blood cells and in our humanized mouse model of P. falciparum malaria,” explained Karine Le Roch, a molecular, cell, and systems biology professor at UCR and the lead author of the study. “We also discovered that MED6-189 proved effective against other zoonotic Plasmodium species, such as P. knowlesi and P. cynomolgi.”
MED6-189 is a synthetic compound inspired by substances derived from marine sponges, synthesized by Christopher Vanderwal’s lab, a professor specializing in chemistry and pharmaceutical sciences at UC Irvine.
“Many effective antimalarial drugs are natural products or closely related to them,” he highlighted. “Artemisinin is a prime example, initially sourced from the sweet wormwood plant, and it plays a crucial role in malaria treatment. MED6-189 is closely related to a different class of natural products known as isocyanoterpenes, which appear to affect multiple pathways in P. falciparum. This multidimensional targeting is advantageous since targeting a single pathway might allow the parasite to rapidly develop resistance.”
Researchers from GSK, a pharmaceutical firm in Spain, discovered that administering MED6-189 to mice infected with P. falciparum successfully eliminated the parasite from the mice. Collaborating with Choukri Ben Mamoun, a professor at the Yale School of Medicine specializing in medicine and microbial pathogenesis, the team evaluated the compound against P. knowlesi, a malaria-causing parasite in monkeys, and confirmed it effectively eradicated the monkey’s infected red blood cells.
The next phase involves the team continuing to refine MED6-189 and verifying the actions of the altered compound through a systems biology approach. This research framework seeks to broadly understand biological systems and the interactions among various living organisms and cells on a larger scale.
Le Roch, Vanderwal, and Ben Mamoun were also supported by additional scientists from the Stowers Institute for Medical Research in Kansas City, Missouri; GSK; and the University of Georgia during this research.
This study received funding from a grant to Le Roch, Vanderwal, Ben Mamoun, and the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health. At UCR, Le Roch oversees the Center for Infectious Disease and Vector Research.
The research paper is titled “A Potent Kalihinol Analogue Disrupts Apicoplast Function and Vesicular Trafficking in P. falciparum Malaria.”
