Clemson University researcher James Morris has received a four-year, $1.77 million grant from the National Institutes of Health to identify compounds that interfere with or prevent a group of deadly parasites from getting the nutrients they need to survive.
The research could lead to better drugs to treat or even prevent three devastating diseases that sicken, disfigure and kill millions of people worldwide, including in the United States.
Morris and a multidisciplinary team of scientists from the University of Wisconsin-Madison, Ohio State University and Brigham Young University will test 100,000 different molecules to see whether they interfere with the way kinetoplastid parasites consume and metabolize glucose. This simple sugar is a key source of energy.
The study will include two parasites and might impact the treatment of a third. Trypanosoma brucei causes African sleeping sickness, an illness that is fatal if left untreated. Leishmania causes a spectrum of illness, from unhealing and potentially disfiguring skin sores that have afflicted U.S. troops in the Middle East to deadly infections of the liver and spleen. While not part of this study, findings might impact the treatment ofTrypanosoma cruzi infections, which lead to Chagas disease, a disease found in the Americas that can cause life-threatening heart problems decades after the initial exposure.
The researchers will evaluate molecules that show promise as compounds for medicinal drugs.
“We have genetically engineered live parasites to make sensors. Those sensors enable us to see which parts of the pathway for nutrient uptake and distribution are working and which ones aren’t when we add compounds to them,” said Morris, a professor in the College of Science’s Department of Genetics and Biochemistry and a researcher at Clemson’s Eukaryotic Pathogens Innovation Center.
While the research might provide early leads for medicines, it will definitely help close a significant gap in understanding fundamental parasite biology. Glucose is a critical metabolite that can also regulate critical developmental pathways in parasites. But scientists’ understanding of those areas is extremely limited, especially in living parasites.
“Not only are we going to find things that interfere, but because we can watch the cells in live time as they take up a nutrient and move it around the cell, we’ll learn how they do that,” Morris continued. “We don’t know anything about that right now.”
Insects transmit all three diseases included in the study.
African trypanosomiasis, transmitted by the tsetse fly, has historically been a big problem in sub-Saharan Africa. The development of some new drugs is helping to control it. “I think that if we’re smart, we can manage the disease in humans. But we can’t manage it in animals, and that has an impact of several billion dollars on agriculturally important animals in sub-Saharan Africa,” Morris said.
The American trypanosome causes Chagas disease, which is transmitted through the feces of “kissing bugs.” The Centers for Disease Control estimates that 300,000 people in the U.S. have the disease. Sandflies transmit Leishmania.
“These are called neglected tropical diseases because they are understudied. Yet, they are sneaking up on the U.S., so we better pay attention,” he said. “Three hundred thousand people have what will likely be a lethal disease for them, but they tend to be people who live on the margins, so it’s not front and center.”
Targeting multiple parasites in the same study is unusual.
“Typically, you would try to find molecules that are useful against the African trypanosome, and I’ve spent a lot of time in my career doing that. But with this grant, we’re looking for things that might similarly affect several organisms because we’re going after something fundamental. That fundamental thing is how they acquire nutrients from the host and how they move them around,” Morris said.
Morris is the principal investigator for the project. Other researchers involved are BYU associate professor Ken Christiansen, who will assess the compounds against the parasites; Jennifer Golden, a medicinal chemist at the University of Wisconsin; and Karl Webovetz, the chair of medicinal chemistry and pharmacognosy at Ohio State, who researchers Leishmania.
“After we find these things that interfere with uptake and distribution, then we’re going to see if they kill parasites because they should,” Morris said.
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