Investigators Discover New Antimalarial Compounds to Target Earlier Stage of Infection

With malaria cases spiking in the Democratic Republic of the Congo and in parts of the Greater Mekong Subregion of Southeast Asia, a new study led by investigators at the University of California, San Diego shows that targeting the malaria parasite at an earlier stage in its lifecycle may offer a novel approach to the development of antimalarial drugs.

Despite years of progress in global malaria control, progress has stalled in recent years, as 10 African countries reported an increase in malaria cases from 2016 to 2017, according to the World Malaria Report released by the World Health Organization on November 19, 2018.

In 2017 there were 219 million cases of malaria reported worldwid, which contributed to 435,000 deaths. The report noted that 92% of global malaria cases occur in African nations and 5% occur in the South-East Asian nations, with 80% of global cases occurring in 15 African countries and India.

The Plasmodium falciparum malaria parasite found in mosquitoes caused 99.7% of malaria cases in Africa in 2017. Currently available antimalarial drugs work against bloodstream parasite stages, and are often taken prophylactically by travelers to malaria-affected regions. Malaria infections begin in the liver from sporozoites transmitted through mosquito bites, before moving into the blood and causing symptoms such as fever, headaches, and chills.

A new multi-institutional study published on December 7, 2018, in Science details recent research into targeting malaria parasites at the liver stage, with investigators discovering more than 600 compounds capable of killing sporozoites, making them valuable antimalarial drug candidates.

In the new study, investigators extracted Plasmodium berghei parasites, which only infect mice, from more than 1 million mosquitoes. The team removed sporozoites and engineered them to produce firefly luciferase, causing them to glow, and then tested more than 500,000 compounds for their ability to inhibit liver-stage development of luciferase-expressing parasites.

They found that 631 compounds stopped the glowing in sporozoites, indicating that they had either died or could no longer replicate. The investigators indicate that these 631 compounds are starting points for the development of new antimalarial drugs. The team has made their findings open source, allowing investigators around the world to further research the compounds as potential malaria drug candidates.

The investigators are hopeful that this research will eventually lead to an antimalaria drug but noted that there are challenges in development.

“It may not be obvious, but if you don’t get malaria in the first place, you aren’t going to die from it—most deaths are because people can’t be treated in time or are misdiagnosed,” said the study’s lead author Elizabeth Winzeler, PhD, professor of pharmacology and drug discovery in the department of pediatrics, and director of translational research at UC San Diego Health Sciences Center for Immunity, Infection, and Inflammation, in an interview with Contagion®. “Of course, there are challenges to protecting people with drugs. No one will want to take daily pills to avoid malaria, so thinking about formulation and how this fits into an elimination strategy will be important. It could ultimately be cheaper to give everyone a $100 injectable and clear malaria from a region, than having to go back over and over again with a $10 course of chemotherapy.”

The study was supported with grants from the National Institutes of Health, the Bill and Melinda Gates Foundation’s Malaria Drug Accelerator—an international consortium focused on speeding drug development—and the Medicines for Malaria Venture.

“Support from the Bill and Melinda Gates Foundation, as well as other funders, has been helpful in the past and will be helpful in the future,” said Dr. Winzeler. “The rise in cases suggests that eliminating malaria will not be easy and that new, innovative strategies may be needed.”