Team Science leads to antimalarial drug discovery

Researchers have discovered a new chemical compound called MED6-189 that is a powerful inhibitor against parasites that are resistant to commonly used antimalarial drugs. The high potency, excellent therapeutic profile and unique mode of action of MED6-189 make it an excellent addition to the anti-malaria drug pipeline, the researchers said.

The study, funded by the National Institutes of Health, was published in Science.

Despite advances in the prevention and treatment of malaria, the disease remains one of the greatest threats to public health worldwide. According to the World Health Organization, the disease caused an estimated 247 million clinical cases and 619,000 deaths in 2022 World Malaria Report 2023.

One of the biggest challenges in fighting malaria is the parasite's resistance to commonly used antimalarial drugs, said Choukri Ben Mamoun, PhD, professor of medicine (infectious diseases), microbial pathogenesis and pathology at the Yale School of Medicine (YSM) and corresponding author of the study.

Aiming to develop a new drug that is easy to manufacture, potent, and effective against drug-sensitive and drug-resistant strains of malaria, researchers from academic laboratories at YSM, the University of California, Irvine, and the University of California, Riverside, utilized a multidisciplinary approach to understand how MED6-189, a structural analogue of a sea sponge secondary metabolite, works.

“This study represents a true systems biology approach to antimalarial drug discovery and is an excellent example of collaborative scientific teamwork that incorporates expertise from multiple institutions and disciplines,” said Amy Bei, PhD, associate professor of epidemiology (microbial diseases) at the Yale School of Public Health and co-author of the study.

This is what the researchers found out Plasmodium falciparumThe pathogen responsible for the most severe form of human malaria, MED6-189, could inhibit both the asexual development of the parasite in the blood and its ability to sexually differentiate, a crucial step in the transmission of malaria.

Because MED6-189 targets multiple processes, the likelihood of the parasite developing resistance to it is low. “To render the compound ineffective, the parasite would have to alter multiple genes and metabolic functions, making resistance much less likely,” said Ben Mamoun.

This unique ability of MED6-189 could also reduce the need for additional drugs, thereby reducing the potential for increased toxicity, he said.

Both Bei and Ben Mamoun emphasize the urgent need to further optimize this class of compounds and identify new antimalarials.

“Given emerging partial resistance to artemisinin-based combination therapies worldwide and, alarmingly, in Africa, where the burden of the disease is greatest, identifying and validating promising new antimalarial guidelines requires a comprehensive, collaborative approach to address this critical challenge,” Bei said.

“Malaria persists, and given widespread resistance, we need to combine our efforts to develop better therapeutic strategies,” said Ben Mamoun. “This compound could act on its own as a combination therapy, typically using multiple drugs to target a single organism and reduce the risk of resistance, similar to what we do with HIV and other diseases.”

Other authors of the article include Zeinab Chahine, Steven Abel, Thomas Hollin, Griffin Lee Barnes, Jonathan Chung, Mary Elizabeth Daub, Isaline Renard, Jae Yeon Choi, Pratap Vydyam, Anasuya Pal, Magdalena Alba-Argomaniz, Charles Banks, Jay Kirkwood, Anita Saraf, Isabel Camino, Pablo Castaneda, Maria Cuevas, Jaime De Mercado-Arnanz, Elena Fernandez-Alvaro, Adolfo Garcia-Perez, Nuria Ibarz, Sara Viera-Morilla, Jacques Prudhomme, Chester Joyner, Laurence Florens, Christopher Vanderwal and Karine Le Roch .

The Yale School of Medicine's Division of Internal Medicine in Infectious Diseases provides comprehensive and innovative patient care, research and educational activities for a broad spectrum of infectious diseases. Find out more at Infectious diseases.