While cryptosporidiosis, infection by the protist parasite Cryptosporidium, is rare in the U.S., it is a common cause of deadly diarrhea in other parts of the world. The only FDA-approved treatment for the infection, nitazoxanide, doesn’t work well in immunocompromised and malnourished children, the group most vulnerable to the pathogen. This has led to cryptosporidiosis being called a “truly neglected tropical disease.”
Now, researchers have identified two new potential drugs that reduced parasite numbers in infected calves and immunocompromised mice. The results were published in Science Translational Medicine on Oct. 23.
Scientists from the University of Dundee in Scotland and the University of Vermont had previously worked with collaborators to identify a new target for antimalarial drugs, lysyl-tRNA synthetase. Because the organism that causes malaria, Plasmodium, is related to Cryptosporidium, the team found that a drug they synthesized targeting lysyl-tRNA synthetase worked on both pathogens.
Lysyl-tRNA synthetase is an enzyme responsible for binding the amino acid lysine to tRNA. The tRNA molecule then binds to the ribosome, which takes the lysine and uses it to build new proteins. Because lysine is a common ingredient in many proteins, shutting down this enzyme interferes with normal protein synthesis in the protist.
The lead drug from that earlier work, DDD706, had to be scrapped for cryptosporidiosis because it was too toxic in mice, the authors reported in their new paper. They decided to home in on Cryptosporidium’s lysyl-tRNA synthetase specifically to see if they could find effective new treatments against it.
The team ultimately settled on two molecules, DDD489 and DDD508, that bind to lysyl-tRNA synthetase and inhibit its activity. When given 10 milligrams per kilogram of the drugs twice a day for one week, infected mice saw their parasite load reduced by almost 100%. When tested in calves, parasite levels in feces dropped dramatically due to treatment, but didn’t for calves given placebo.
The two drug candidates are now moving forward to preclinical safety studies, the researchers said in the paper.
Novartis teamed up with the Bill & Melinda Gates Foundation in 2018 to advance its own cryptosporidiosis drug, KDU731. However, that drug is no longer being developed, a Novartis spokesperson confirmed to Fierce Biotech in an email. Instead, the Big Pharma is now pursuing a similar drug called EDI048, the spokesperson said.