Anti-malarial compounds could help treat deadly diarrheal disease
Study finds the compounds block malaria and Cryptosporidium parasites in same way, paving the way to new treatments
By Liz Touchstone, University of Illinois at Urbana-Champaign
Credit: Sumiti Vinayak
Intestinal tissue infected with Cryptosporidium, with arrows pointing to the parasites.
A team of scientists has discovered a new way of targeting the pathogen that causes a deadly form of diarrheal disease.
Led by researchers at the ӳý of MIT and Harvard and elsewhere, the new study revealed that compounds used for malaria treatment also kill the intestinal parasite Cryptosporidium, a leading cause of diarrheal disease and death in children that has no cure.
The compounds, called bicyclic azetidines, specifically target an enzyme responsible for protein production within Cryptosporidium, the authors report in the journal .
“There’s an urgent need because young children are dying of this diarrheal pathogen, and there’s no effective medicine to treat the infection nor vaccine to prevent the disease,” said the manuscript lead author, Sumiti Vinayak, a pathobiology professor at the University of Illinois Urbana-Champaign. “Immunocompromised patients and agricultural animals, especially young calves, are also very susceptible to Cryptosporidium. This is the first time we have had validation of a compound working on a specific target in this parasite.”
In previous work, ӳý scientists searched for potential new anti-malarial drugs by scanning the ӳý’s Diversity-Oriented Synthesis (DOS) library, a collection of compounds designed to emulate small molecules found in nature but absent in pharmaceutical industry libraries. They identified some that kill the malaria parasite in a unique way, by inhibiting an enzyme in the parasite that helps it make proteins. The researchers then teamed up with Chris Huston at the University of Vermont, who set up an assay to test whether antimicrobial compounds could also kill Cryptosporidium.
Parasite killers
The anti-malarial bicyclic azetidines were most promising and proved very effective at killing the Cryptosporidium parasite in cell cultures, so the researchers next tested them in immunocompromised mice with Cryptosporidium infections. They found that one oral dose a day for four days rid the mice of infection.
“This study provides a new way of targeting Cryptosporidium. Significantly, because we are repurposing compounds from an anti-malarial program in development, it allows us to apply insights from that program to the treatment of cryptosporidiosis,” said co-senior author Eamon Comer, who led the study while at ӳý, along with Huston and Boris Striepen of the University of Pennsylvania. Comer is now working in the biotech industry.
The researchers then performed comprehensive biochemical and genetic studies to determine how the compounds attacked the parasite. They found that the bicyclic azetidines targeted an enzyme that makes transfer RNA, the molecule that carries amino acids when the cell makes proteins. The Cryptosporidium enzyme is very similar to that of the parasite that causes malaria, but different from the analogous enzyme in humans, Vinayak said, making it an effective drug target.
“This is the first time that the mechanism of action of an anti-Cryptosporidium drug candidate has been confirmed,” Vinayak said. “It’s a good stepping stone to find these compounds that we can feed into the drug-development pipeline. Future research will further evaluate safety and clinical effectiveness, but the discovery of a new and potent series of compounds with a known target puts us on a promising path forward in this important effort to develop urgently needed treatments.”
The Bill and Melinda Gates Foundation and the National Institutes of Health supported this work.
Adapted from , University of Illinois Urbana-Champaign.