Fighting Parasitic Flatworms: A New Hope in Medical Research

Parasitic flatworms known, as flukes or trematodes, are responsible for some of the most debilitating neglected tropical diseases (NTDs) affecting billions of people worldwide.

Schistosomiasis, caused by blood flukes, is a significant health risk in many tropical regions. Fascioliasis, caused by liver flukes, impacts both livestock and humans, leading to severe economic and health problems. Compounding these issues, current treatments like praziquantel (PZQ) have limitations.

“Although praziquantel is pretty good, it does have some drawbacks, including not working against the liver fluke that causes fascioliasis,” says Jonathan S. Marchant, MA, PhD, Marcus Professor and Chair of Cell Biology, Neurobiology and Anatomy.

The need for more effective treatments and a growing resistance to currently available drugs has pushed researchers to find new solutions. This challenge was the driving force behind innovative research conducted at the Medical College of Wisconsin (MCW) aimed at discovering new treatments for fluke infections.

A Breakthrough in Treating Neglected Tropical Diseases

In a groundbreaking study, Dr. Marchant and his team identified a new class of compounds called benzamidoquinazolinones (BZQs) that show promise as broad-spectrum treatments for trematode infections in humans.

Their research, published in Nature Structural & Molecular Biology, reveals that BZQs can effectively target and neutralize all species of flukes by activating a specific ion channel known as TRPM_PZQ. This broad-spectrum activity suggests that a single treatment could potentially combat multiple fluke infections, simplifying treatment protocols and reducing costs.

“We found a new type of molecule with a different structure that is able to sit in the binding pocket of that liver fluke ion channel target and, unlike praziquantel, activate it,” says Dr. Marchant. “For the first time, we have a new class of drugs that target this ion channel in fascioliasis.”

The publication about this research, titled “Target-based discovery of a broad-spectrum flukicide,” has already garnered significant attention in the scientific community for its potential to improve treatment for parasitic infections.

A Discovery That Could Help Billions

The researchers began their study by conducting high-throughput screening to find compounds that could activate the schistosome TRPM_PZQ channel. By targeting the channel, the researchers aimed to disrupt the nervous and muscle systems of the trematodes. This initial screening led to identifying BZQs as potent activators.

The team, led by Daniel Sprague, MD, PhD ’21, postdoctoral fellow at MCW, then conducted structure-activity relationship (SAR) studies to help them understand how the chemical structure of BZQs related to their biological activity. By tweaking the chemical structure, they enhanced the compounds’ effectiveness, making them strong candidates for treatment.

The optimized BZQ compounds were then tested on liver flukes, and the results were promising. The BZQs caused prolonged paralysis and significant damage to the parasite’s outer layer, known as the tegument. This damage is vital because the tegument protects the parasite from the host’s immune system and absorbs nutrients. By damaging the tegument and causing paralysis, BZQs effectively neutralize the flukes, preventing them from harming their hosts.

Next, the researchers plan to further refine the BZQ compounds and conduct comprehensive clinical testing to ensure their safety and effectiveness in humans and animals. Ultimately, they aim to develop a widely available and affordable treatment that can be used in regions where these diseases are common, significantly reducing the burden of trematode infections.

“These NTDs caused by trematode infections affect 1.7 billion people, with even more at risk. While it may not yet be an American problem, it is definitely a worldwide issue,” Dr. Sprague says.