A Virginia Tech research team has discovered an innovative way to inhibit the parasite that causes African sleeping sickness.
The breakthrough came when the team, led by Fralin Life Science Institute researcher Zac Mackey, discovered that the parasite Trypanosoma brucei uses a distinct method to perform a biochemical process known as phosphorylation.
This finding will be published in a forthcoming issue of the journal Cell Cycle, where it is also highlighted in the News and Views section by George-Lucian Moldovan, an assistant professor in the department of biochemistry and molecular biology at Penn State University.
“Our findings will allow us to take advantage of a key biochemical difference that can be used to cure this deadly parasitic disease,” said Mackey, an assistant professor in the College of Agriculture and Life Sciences. “The parasite causes thousands of deaths per year in sub-Saharan Africa, where about 70 million people are at risk, and has a devastating effect on the agricultural economy of 36 countries in this region.”
“The most important finding of this exciting paper is the fact that the newly discovered mechanism regulating Trypanosoma proliferation is unique to the parasite,” said Moldovan, who was not involved in the research. “This will allow the discovery of drugs that can inhibit Trypanosoma without affecting human cells.”
By screening compound libraries at the Virginia Tech Center for Drug Discovery, Mackey’s team was also able to identify a molecule known as AZ960 (typically used for anticancer therapies) that can block the unique process and shut down the parasite. The findings were published in the journal Bioorganic and Medicinal Chemistry.
“These studies really put us in a position to start testing AZ960 in mouse models to cure Trypanosoma brucei infections and to begin chemical modifications to maximize the molecule’s potency,” said Mackey, a member of the Fralin Life Science Institute’s Vector-borne Disease Research group.
Mackey partnered with Webster Santos, an associate professor of chemistry in the College of Science for the molecule screening. Other co-authors include Mackey’s former graduate students Ana Lisa Valenciano and Aaron Ramsey.
“It is amazing how a potential anticancer drug can be repurposed to kill these parasites,” said Santos. “The hard work now begins — we need to make them more selective for Trypanosoma brucei over human cells. This is a task that we can achieve at the Virginia Tech Center for Drug Discovery.”
Trypanosoma brucei is carried by the tsetse fly, which is found only in rural Africa, according to the Centers for Disease Control and Prevention. When the parasite infects a human host, it causes sleeping sickness, which progresses to a lethal and pathological brain disease if left untreated.
Previous drugs aimed at killing the parasite have caused undesirable side effects in the human host, including death, fever, rash, and vomiting depending on the drug.
There is a dire need for drugs that are less toxic to patients and more effective at curing this lethal disease.