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Chem major battles malaria parasite

By Chris Lydgate ’90 on April 24, 2017 12:44 PM

THE ADVERSARY. The malevolent malarial parasite plasmodium falciparum is responsible for killing more than 400,000 people every year. Most of the victims are children.

For her senior thesis, chemistry major Rose Gonoud ’17 squared off against one of humankind’s most ancient and implacable adversaries: Plasmodium falciparum, the parasite that causes malaria.

Plasmodium is a truly diabolical foe, responsible for the death of more than 400,000 people every year, according to the World Health Organization. It also has an extraordinary ability to mutate, developing resistance to many of the drugs currently used to fight it.

One technique for overcoming this resistance is to start with an old drug and fine-tune it to attack the newer strains of the parasite. Rose focused her research on decoquinate (DQ), a drug developed in the 1960s to combat bacterial infections in chickens. Last year, researchers made the surprising discovery that decoquinate is also effective against malaria, making it an attractive candidate for drug development. Unfortunately, there’s a problem. DQ is insoluble—it doesn’t dissolve in the bloodstream, making it impossible to deliver the drug to the organs where the parasite usually hangs out. Rose’s mission was to see if she could find a way to make the drug more soluble without sacrificing its malaria-killing power.

Rose grew up in upstate New York and came to Reed intending to major in psychology. “I was bad at chemistry in high school,” she chuckles. “It was my Achilles heel.” But her attitude about the discipline was transformed after taking intro chem with Prof. Arthur Glasfeld. Last summer she did a medicinal chemistry internship with Gilead Sciences in Seattle, and wanted to explore the field for her thesis project.

Prof. Alan Shusterman suggested she work with Dr. Aaron Nilsen, a former visiting professor at Reed who now does malaria research in the Experimental Chemotherapy Laboratory at Oregon Health and Science University across the river. “I knew immediately that I wanted to do this,” she says.

DQ operates by latching onto a protein in the parasite’s mitochondria—its microscopic power supply. This interrupts the electron transport chain, a key energy production pathway, and gums up the germ’s ability to synthesize ATP . “The plasmodium just runs out of gas,” she says.

As she dug into her project, Rose realized that there were actually three reasons why DQ is insoluble. The first is something that earlier researchers had noticed: The DQ molecule consists of a quinolone core and a long tail that is hydrophobic, or greasy—and as every dishwasher knows, grease won’t dissolve in water. But there are other reasons, too. The core also contains an open hydrogen bond, which tends to attract other DQ molecules, forming big clumps that don’t mix with water. Finally, the core features central rings that also tend to make DQ molecules cling to each other in an interaction known as “pi stacking.”

Rose began to suspect that the hydrogen bonding and the pi stacking were even more important to DQ’s insolubility than the greasy tail. And she realized something else—“This was fixable,” she says.

Decoquinate

The decoquinate molecule consists of a quinolone core and a long hydrophobic tail.

Starting in the fall, she used chemical ingenuity to tinker with the structure of the core, substituting different strings of atoms in an effort to stop the molecules from tangling together like rugby players in a scrum. After several months of intensive effort, Rose succeeded in synthesizing three new derivatives of DQ. Then came the showdown: how would they fare against the plasmodium?

Rose injected the derivatives into test tubes filled with blood teeming with parasites, and anxiously waited for the results. The first compound, dubbed DQ-100, was a dud. But the other two—DQ-331 and DQ-337—proved both soluble and effective at killing the plasmodium. In fact, DQ-337 actually turned out to be more lethal to the germ than DQ.

“I was elated,” Rose says. “There was a lot of excitement in the lab, I remember thinking I had gotten very lucky.”

“This is great work,” says her thesis adviser, Dr. Nilsen. “It’s pretty impressive.”

The DQ compounds that Rose developed are not silver bullets; they are probably not effective enough to be used in the field. But interfering with the plasmodium’s electron transport chain is going to be a key strategy for developing the next generation of antimalarials, Nilsen says.

For her part, Rose says the journey has been exhilarating. “It’s been a lot of fun,” she says. Researchers in the lab are now looking at other ways to shut down the plasmodium. In fact, several other Reed grads are working on the project at OHSU, including Alina Krollenbrock ’12, Emma Farley ’13, and Lisa Frueh ’15.

Rose hopes to join them after graduation.