Finding Drugs to Combat Malaria

Each year nearly 600,000 people—mostly children under age 5 and pregnant women in sub-Saharan Africa—die from malaria, caused by single-celled parasites that grow inside red blood cells. The most deadly malarial species—Plasmodium falciparum—has proven notoriously resistant to treatment. But thanks to a novel approach developed by Einstein scientists and described earlier this year in ACS Chemical Biology, researchers can readily screen thousands of compounds to find those potentially able to kill P. falciparum.

This colorized photomicrograph (x22,275) shows the young trophozoite stage of a single-celled Plasmodium falciparum parasite that has infected a red blood cell. Malaria is spread to humans by species of the Anopheles mosquito. P. falciparum initially multiplies in liver cells and later spreads to the blood. Trophozoites such as this one reproduce asexually, forming 8 to 32 new parasites in each infected red cell within 48 hours. These red cells ultimately burst and release the parasites, causing malarial symptoms, including shaking, chills and fever.
This colorized photomicrograph (x22,275) shows the young trophozoite stage of a single-celled Plasmodium falciparum parasite that has infected a red blood cell. Malaria is spread to humans by species of the Anopheles mosquito. P. falciparum initially multiplies in liver cells and later spreads to the blood. Trophozoites such as this one reproduce asexually, forming 8 to 32 new parasites in each infected red cell within 48 hours. These red cells ultimately burst and release the parasites, causing malarial symptoms, including shaking, chills and fever.

Scientists have known for more than a decade that malaria parasites have an Achilles’ heel: Like all cells, they require two key building blocks—purines and pyrimidines—to synthesize their DNA and RNA. But malaria parasites can’t synthesize purines on their own. Instead, they must import purines from the host red blood cells that they invade. A parasite protein called PfENT1 transports purines from the blood cells into the parasites. So drugs that block PfENT1 could conceivably kill the parasites by depriving them of purines they need—but an experimental approach for identifying PfENT1 inhibitors didn’t exist, until now.

Einstein’s Myles Akabas, M.D., Ph.D., developed a novel yeast-based high-throughput assay for identifying inhibitors of the PfENT1 transporter. Dr. Akabas worked with two Medical Scientist Training Program students in his lab (I. J. Frame and Roman Deniskin) as well as colleagues at Einstein (Ian M. Willis, Ph.D., a professor of biochemistry and of systems & computational biology, and Robyn D. Moir, Ph.D., an instructor in the department of biochemistry) and at Columbia University (Donald W. Landry, M.D., Ph.D., and David A. Fidock, Ph.D.). The researchers used their technique to screen 64,560 different compounds and identified 171 compounds that showed antimalarial potential. Studies of nine of the most potent compounds showed that they kill P. falciparum parasites in laboratory culture.

“We’ve shown that the PfENT1 transporter is a potential drug target for developing novel antimalarial drugs,” says Dr. Akabas, senior author of the ACS Chemical Biology paper and a professor of physiology & biophysics, of medicine and in the Dominick P. Purpura Department of Neuroscience at Einstein. “By using our rather simple approach, scientists could create similar high-throughput screens to identify inhibitors for killing other parasites that rely on transporters to import essential nutrients.”

The National Institutes of Health recently awarded Dr. Akabas and his Columbia University collaborators a five-year, $3.45 million grant to use his high-throughput assay to find and develop antimalarial drugs. Einstein has applied for patents to cover this assay.