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December 21, 2024 – A groundbreaking study published in Nature Communications has solved a decades-long scientific mystery, opening the door to potentially more effective treatments for leishmaniasis, a deadly parasitic disease affecting millions worldwide. The research, led by Michael Zhuo Wang, a professor of pharmaceutical chemistry at the University of Kansas School of Pharmacy, sheds light on a crucial biochemical pathway in the parasites responsible for visceral leishmaniasis (VL), a disease that claims about 30,000 lives annually.
Leishmaniasis, caused by the Leishmania parasite, has long been a challenge to treat, with current treatments being limited and often ineffective. The new study reveals that the parasite makes ergosterol, a lipid sterol also found in fungi, which serves a similar role to cholesterol in humans. This discovery explains why scientists once considered using azole antifungal drugs, which target a vital enzyme in ergosterol production, as a potential treatment for VL.
However, early attempts to use azoles were largely unsuccessful, leaving researchers puzzled. Azoles work against fungi because they target an enzyme called CYP51, involved in ergosterol biosynthesis. Since Leishmania parasites also produce ergosterol, the natural assumption was that azoles should work. But some azoles had no effect, while others showed only limited success in treating VL in the lab and clinical trials.
Wang, who had long been intrigued by this puzzle, and his team at the University of Kansas have now uncovered the answer: the Leishmania parasite uses a different enzyme, known as CYP5122A1, for ergosterol production. This enzyme is a critical target for azoles, meaning that antifungal drugs can be more effective against leishmaniasis if they inhibit this newly identified enzyme, in addition to the traditional CYP51 enzyme.
“This is the key discovery,” Wang said. “To effectively treat Leishmania, we need to focus on this new enzyme, CYP5122A1. Azoles that block this enzyme could hold the key to successfully treating VL.”
Wang’s lab was able to demonstrate that the CYP5122A1 gene encodes a crucial sterol C4-methyl oxidase in Leishmania, which plays an essential role in the biosynthesis of ergosterol. Through extensive biochemical analysis, the researchers confirmed that targeting this enzyme would disrupt the parasite’s ability to produce ergosterol, thereby stopping its growth.
The discovery has significant implications for the development of new, more effective treatments for VL. Researchers now suggest that existing antifungal azoles can be repurposed to target the CYP5122A1 enzyme. This strategy could lead to breakthroughs in drugs that save thousands of lives each year.
The study was a collaborative effort between the University of Kansas, Texas Tech University, and Ohio State University, with support from the U.S. National Institute of Allergy and Infectious Diseases and the U.S. Department of Defense.
“This finding is a game-changer for neglected tropical diseases like leishmaniasis,” said Wang. “By targeting this new enzyme, we have a clearer path forward for developing treatments that could make a real difference in global health.”
The research team’s work provides an exciting new avenue for the treatment of VL and other parasitic diseases, offering hope for millions of people at risk of these debilitating and often fatal infections.
