UNIVERSITY PARK, Pa. — More than 600 promising new antimalarial drug candidates that inhibit the malaria parasite at an earlier stage in its lifecycle than most current drugs have been identified from a screen of more than 500,000 chemical compounds. A new study, published Dec. 7 in the journal Science, by an international team of researchers, including two from Penn State, reveals a new set of chemical starting points for the first drugs to prevent malaria instead of just treating its symptoms. The study also begins to explore how the most potent of these compounds work.
“In many ways, the search for new malaria drugs has been a search for something akin to aspirin — it makes you feel better but doesn’t necessarily go after the root of the problem,” said Elizabeth Winzeler, professor of pharmacology and drug discovery at University of California San Diego School of Medicine and leader of the research team.
Most malaria drugs are designed to reduce symptoms after infection. They block replication of the disease-causing parasites in human blood, but they don’t prevent infection or transmission via mosquitoes. The current study took a different approach: targeting the malaria parasite at an earlier stage in its lifecycle that occurs right after a mosquito bite, when it initially infects the human liver, rather than waiting until the parasite is replicating in blood and making a person ill.
The team at UCSD spent two years extracting malaria parasites from hundreds of thousands of mosquitoes, using robotic technology to systematically test more than 500,000 chemical compounds for their ability to shut down the malaria parasite at the liver stage. After this immense initial screen, the researchers confirmed the potency of the compounds that killed or blocked the replication of parasites and weeded out the ones toxic to liver cells. This narrowed the list to 631 promising compounds that could form the basis for new malaria prevention drugs — drugs that could block a malaria infection before symptoms begin, and prevent transmission to the blood, mosquitoes and other people.
Most cases of malaria are caused by the mosquito-borne parasites Plasmodium falciparum, which causes the most lethal form of malaria, or Plasmodium vivax, which, although not as lethal, causes a recurrent form of malaria that affects millions of people in southeast Asia. Globally, malaria cases are on the rise, according to a new report from the World Health Organization (WHO). There were 219 million cases in 2017, compared to 217 million the previous year. In 2017, approximately 435,000 people died of the disease. The malaria parasites are also developing resistance to some common drugs, so the need for more effective antimalarial drugs is more pressing than ever.
For safety, in the initial screens, the team used a related parasite called Plasmodium berghei, which can only infect mice. They then tested the smaller subset of 631 compounds against the two human strains. In addition to the liver stage, the researchers also tested the compounds against parasites in the later blood stage.
“We are most interested in compounds that work against multiple stages of the parasite,” said Manuel Llinás, professor of biochemistry and molecular biology and of chemistry at Penn State and an author of the paper. “From the perspective of drug development, the more potent a compound can be at both the early liver stage and the later blood stages of infection, the better chance it has of completely eliminating the parasite.”
Llinás, and Edward Owen, a research technologist in his lab, tested 13 of the most potent compounds to explore how they work to kill malaria parasites. They specifically examined whether these compounds affect the parasite’s metabolism using a mass spectrometry-based method developed in the Llinás lab.
“What is striking is that, although these compounds don’t look anything like each other, ten of the 13 all target parts of the same pathway: the mitochondrial electron transport chain,” said Llinás. “We knew this pathway was susceptible, and some current drugs already target it, in the blood stage. These new results suggest that this pathway is also a highly susceptible part of metabolism during the liver stage. Interestingly, the other three compounds target pathways that have not been worked on before and might provide promising avenues of research for future drug development.”
Next, the research team, many of which are members of an international consortium focused on speeding malaria drug development — the Bill and Melinda Gates Foundation Malaria Drug Accelerator (MalDA) — will continue to explore the mechanism by which many of these 631 compounds work against the malaria parasite. They will also continue the work necessary to develop the compounds into next-generation antimalarial drugs that are safe for human consumption and effective at preventing liver-stage parasites from replicating and bursting out into the bloodstream.
To help speed this effort, the researchers made their findings open source, meaning the data are freely shared with the scientific community.
“It’s our hope that, since we’re not patenting these compounds, many other researchers around the world will take this information and use it in their own labs and countries to drive antimalarial drug development forward,” said Winzeler. “The malaria research community has always been particularly collaborative and willing to share data and resources, and that makes me optimistic that we’ll soon get there too.”
In addition to Winzeler, Llinás and Owen, the research team includes: Yevgeniya Antonova-Koch, Stephan Meister, Matthew Abraham, Madeline R. Luth, Sabine Ottilie, Juan Carlos Jado Rodriguez, Jaeson Calla, Korina Eribez, Cullin McLean Taggard, Andrea L. Cheung, Christie Lincoln, Biniam Ambachew and Dionicio Siegel, UC San Diego; Amanda K. Lukens and Dyann F. Wirth, Harvard University and Broad Institute; Tomoyo Sakata-Kato, Broad Institute; Manu Vanaerschot and David A. Fidock, Columbia University; Steven P. Maher and Amy J. Conway, University of Georgia and University of South Florida; David Plouffe, Yang Zhong, Kaisheng Chen, Case W. McNamara, Maureen Ibanez, Kerstin Gagaring and Yingyao Zhou, Genomics Institute of the Novartis Research Foundation; Victor Chaumeau and François Nosten, Mahidol University and University of Oxford; Fernando Neria Serrano, GlaxoSmithKline; Melanie Rouillier, Francisco-Javier Gamo, Jeremy Burrows and Brice Campo, Medicine for Malaria Venture; and Dennis E. Kyle, University of South Florida.
This research was funded, in part, by the National Institutes of Health, Bill & Melinda Gates Foundation, Medicines for Malaria Venture, Georgia Research Alliance and Wellcome Trust of Great Britain.