Researchers spent two years testing chemical compounds for their ability to inhibit the malaria parasite at an earlier stage in its lifecycle than most current drugs, revealing a new set of chemical starting points for the first drugs to prevent malaria instead of just treating the symptoms.
Most malaria drugs are designed to reduce symptoms after infection. They work by blocking replication of the disease-causing parasites in human blood, but they don’t prevent infection or transmission via mosquitoes. What’s worse, the malaria parasite is developing resistance to existing drugs.
“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, PhD, professor of pharmacology and drug discovery at University of California San Diego School of Medicine.
In a study publishing December 7 in Science, Winzeler and her team took a different approach: targeting the malaria parasite at an earlier stage in its lifecycle, when it initially infects the human liver, rather than waiting until the parasite is replicating in blood and making a person ill.
The team spent two years extracting malaria parasites from hundreds of thousands of mosquitoes and 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 further testing, they narrowed the list to 631 promising compounds that could form the basis for new malaria prevention drugs.
To help speed this effort, the researchers made the 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,” Winzeler said.
Most cases of malaria are caused by the mosquito-borne parasites Plasmodium falciparum or Plasmodium vivax. The parasites’ lifecycle begins when an infected mosquito transmits sporozoites into a person while taking a blood meal. A few of these sporozoites may establish an infection in the liver. After replicating there, the parasites burst out and infect red blood cells. That’s when the person begins to experience malarial symptoms, such as fever, chills and headaches. That’s also when the parasite can be sucked up by a new mosquito and transmitted to another person.
For safety’s sake, Winzeler and team used a related parasite called Plasmodium berghei in the study, which can only infect mice. Their collaborators in New York infected mosquitos with these parasites and every Tuesday, Winzeler’s team would receive a big orange box of mosquitoes by FedEx. On Tuesday afternoons, they would extract the sporozoites, transfer them to plates containing 1,536 tiny divots, or wells, and then carry the plates over to the drug screening facilities at Skaggs School of Pharmacy and Pharmaceutical Sciences at UC San Diego or across the street to the Genomics Institute of the Novartis Research Foundation.