A breakthrough in understanding how a parasite cells ergosterol (its version of cholesterol) may lead to more practical drugs for human leishmaniasis, a parasitic disease that affects about a million people worldwide every year. It kills about 30,000 people.
The findings, reported in , also solve a decades-long scientific puzzle that has prevented drugmakers from successfully using azole antifungals to treat visceral leishmaniasis, or VL.
About 30 years ago, scientists discovered that the 2 kinds of single-celled parasites that cause VL, Leishmania donovani and Leishmania infantum, make the identical lipid sterol, called ergosterol, because the fungus liable to azole antifungals. . These azole antifungals goal a vital enzyme for sterol biosynthesis, called CYP51.
Although not fungi, each species of Leishmania share biochemical similarities with fungi of their plasma membrane, where ergosterol helps maintain cellular integrity and supports many biological functions, much as cholesterol does in humans. .
Michael Zuo Wang, a professor of pharmaceutical chemistry on the University of Kansas School of Pharmacy, said that folks examined the sterol profile of parasites and discovered that they contained mainly ergosterol. “This sterol is the main component of their plasma membrane sterols. The same can be seen in fungi. The membranes of fungal organisms also contain high amounts of ergosterol. To try to prevent this, use antifungal azoles. The original instinct was the way.”
However, scientists were unable to make use of antifungals effectively against VL.
“In the research lab and some clinical trials, some azoles worked a little, and some other azoles didn't work at all,” Wang said. “I finally focused on a scientific question on this sterol pathway – if this parasite also uses ergosterol, you'd think all the antifungal azoles would work against this parasite.”
Along those lines, Wang began his independent research profession as a part of a bunch on the University of North Carolina-Chapel Hill called the Consortium for Parasitic Drug Development.
“We were interested in developing new drugs against neglected tropical diseases,” he said. “One of these diseases is leishmaniasis. The other is African sleeping sickness. Leishmaniasis, which is spread by the sandfly vector in warm climates, is a truly devastating infection of internal organs such as the liver and spleen, as well as the bone marrow. can cause.”
In their latest academic paper, Wang and his colleagues have largely addressed this long-standing scientific query. They show the parasites that cause leishmaniasis are impaired for his or her ergosterol biosynthesis through a special pathway, called the CYP5122A1 enzyme. Therefore, azole antifungals targeting the CYP5122A1 enzyme in addition to the standard CYP51 pathway must be more practical within the treatment of leishmaniasis.
“So those azoles don't work very well against Leishmania unless you have an azole that also inhibits the new pathway, CYP5122A1,” Wang said. “Then, all of a sudden, they become very active against Leishmania. That's the key discovery in this research — we found the real drug target in Leishmania. You really need to kill this new enzyme, 22A1. To prevent parasites.”
Wang's lab at KU demonstrated the CYP5122A1 gene to encode a vital sterol C4-methyl oxidase within the Leishmania parasite through extensive biochemical characterization.
“This involves defining its biochemical function – what this enzyme does in terms of sterol biosynthesis,” he said. “We deciphered its biochemical function, and elucidated its role in the ergosterol biosynthesis pathway.”
Already, researchers are publishing follow-up scholarship and discoveries based on their latest advances in understanding the sterol synthesis pathway in parasites. Drugmakers and researchers should develop treatments that concentrate on CYP5122A1, he said. This must be more practical in helping people avoid leishmania, Wang said.
“This tells us how we should repurpose these existing antifungal azoles by screening against this new target,” said the KU researcher. “Those who actually block this new target should have a better chance of working against Leishmania infection.”
Wang's co-authors on the KU School of Pharmacy were doctoral students Yiro Jin and Mei Feng, who served as lead authors, and doctoral student Lingli Qin within the Department of Pharmaceutical Chemistry as a co-author; director Chimini Perera and doctoral student Indiwara Manasinghe from KU's Synthetic Chemical Biology Core Laboratory; Philip Gao, director of KU's Protein Production Group; and Judy Keju Wu, associate teaching professor of pharmacy practice.
The KU researchers included Kai Zhang, Sumrita Basu, Yu Ning, Robert Madden, Hannah Burks and Salma Waheed Sheikh from Texas Tech University. and Carl Werbowitz, Arlene Joachim, Jonan Lee and April Joyce from The Ohio State University.
The study was supported partially by the US National Institute of Allergy and Infectious Diseases, the US Department of Defense and the KU Centers of Biomedical Research Excellence (COBRE).