Milwaukee, Jan. 6th, 2022 – Neglected tropical diseases (NTDs) represent a group of about 20 conditions that affect more than a billion people worldwide. They are diseases of poverty that impact people living in the poorest communities in terms of wealth, infrastructure, and access to sanitation. They take health away; and for children, their chances of staying in school and earning a living.
One of the most impactful NTDs is schistosomiasis (the ‘snail fever’, Bilharzia). This disease is caused by infection with parasitic worms known as schistosomes that live in the blood of their host where they lay eggs that cause tissue damage. Schistosomiasis is treated using a drug called praziquantel, discovered in the 1980s. However, for over forty years, there has not been understanding of how this drug works. This has been a roadblock to designing new therapies for both schistosomiasis as well as other diseases caused by parasitic flatworms.
In work recently published in Science Translational Medicine, independent teams from the Medical College of Wisconsin (MCW) and Texas Biomedical Research Institute have finally solved this mystery. Both groups of researchers converged on a protein within these worms that is activated by praziquantel to help eliminate worms from the body.
“Praziquantel is one of the most important clinical drugs that people have not heard about,” says Jonathan Marchant, PhD, professor, MCW, senior author of one of the studies. “This is because it is a drug used to treat a neglected tropical disease, which unfortunately attracts less research and investment despite its burden on people worldwide.”
Marchant’s group demonstrated that praziquantel binds with high specificity to a type of ion channel, known as a transient receptor potential (TRP) channel. Activation of this worm TRP channel by praziquantel causes rapid paralysis and damage to the parasite triggering elimination of worms from the body.
By collaborating with scientists from Merck KGaA, Darmstadt, Germany, the company involved in the discovery of praziquantel, the team mapped the binding site of praziquantel and a detailed model of the molecular interactions necessary for activating the channel was validated in Marchant’s laboratory.
“Having a detailed understanding of how this drug engages this target at the molecular level provides new opportunities for drug development to help combat this debilitating disease of children” says Lukas Friedrich, co-first author of this research and scientist at Merck KGaA, Darmstadt, Germany.
This new understanding of praziquantel has already illuminated why some parasitic worms show natural insensitivity to praziquantel, while others are highly sensitive to this drug.
“Tiny variation in this binding pocket stops praziquantel from working,” says Sang-Kyu Park, staff scientist, MCW, first author of this research. “We demonstrate that such variation occurs naturally in a type of parasitic flatworm that causes disease of cattle and livestock, and this may occur for schistosomiasis too, causing concern that praziquantel may stop working in the clinic.”
This conclusion was reinforced by work co-published in the same issue of Science Translational Medicine from Tim Anderson’s group from the Texas Biomedical Research Institute. The Texas Biomed group studied a population of worms that showed resistance to praziquantel exposure, applying state-of-the-art genetic analyses to identify regions within the worm’s genome that underpinned this insensitivity to drug treatment. Remarkably, their analyses identified the very same TRP channel, providing independent verification of the importance of this particular target.
“We have two independent papers using completely different methods coming to the exact same conclusions,” says Tim Anderson, PhD, professor, Texas Biomed, senior author of the Texas Biomed study. “Because the papers are being published back-to-back, I think they will be taken very seriously. Research on TRP channels of mammals won the Nobel prize in Physiology or Medicine in 2021. That these channels are also involved in mode of action of a critically important antiparasitic drug is extremely exciting.”
“This research will be highly impactful for treating schistosomiasis in the field”, adds Thomas Spangenberg, Head of Global Health Open Innovation and Drug Discovery at the Global Health Institute of Merck KGaA, Darmstadt, Germany. “Finally understanding the mechanism of action of praziquantel will help catalyze new research that will support control and elimination programs for schistosomiasis worldwide. This is an important breakthrough.”
Dr. Jonathan Marchant is the Marcus Professor and Chair of Cell Biology, Neurobiology and Anatomy at the Medical College of Wisconsin. Work in the Marchant laboratory is supported by the Marcus Family and funding from the National Institute of Allergy and Infectious Diseases (R01AI145871).
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About the Medical College of Wisconsin
With a history dating back to 1893, The Medical College of Wisconsin is dedicated to leadership and excellence in education, patient care, research and community engagement. More than 1,400 students are enrolled in MCW’s medical school and graduate school programs in Milwaukee, Green Bay, and Central Wisconsin in. MCW’s School of Pharmacy opened in 2017. A major national research center, MCW is the largest research institution in the Milwaukee metro area and second largest in Wisconsin. In the last ten years, faculty received more than $1.5 billion in external support for research, teaching, training and related purposes. This total includes highly competitive research and training awards from the National Institutes of Health (NIH). Annually, MCW faculty direct or collaborate on more than 3,100 research studies, including clinical trials. Additionally, more than 1,650 physicians provide care in virtually every specialty of medicine for more than 2.8 million patients annually.
Science Translational Medicine
Mechanism of praziquantel action at a parasitic flatworm ion channel
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