by Justin Jackson , Medical Xpress

Illustration of the roles of drug properties in penetrating Cryptosporidium in the gut. Credit: Nicola Caldwell, 2024

Scientists from the University of Dundee and the University of Vermont have identified two compounds that could lead to effective treatments for cryptosporidiosis (Crypto). The disease disproportionately affects children under the age of five who are experiencing malnutrition, often fatally, making it a leading cause of death among children worldwide.

Crypto is caused by a very hard to eliminate parasite. The only existing medication, nitazoxanide, has limited approval and efficacy in immunocompromised patients and malnourished children. With no vaccine available, no reliably effective treatment, and hundreds of thousands of lives in jeopardy each year, there is an urgent need for new therapeutics..

Crypto parasites reside within an intracellular but extracytoplasmic parasitophorous vacuole in the epithelial cells of the small intestine. Essentially, the parasite makes a small cocoon out of cell tissue from the intestinal wall and forms a secondary protective shell within that cocoon.

This unique configuration makes drug targeting a challenge. Effective treatments must penetrate both the intestinal cell membrane and the protective layer to reach the parasite inside.

In a study, “Cryptosporidium lysyl-tRNA synthetase inhibitors define the interplay between solubility and permeability required to achieve efficacy,” published in Science Translational Medicine, researchers detail the complicated nature of combating Crypto and test strategies for overcoming those challenges. The results establish that balancing solubility and permeability is essential for optimizing the efficacy of anti-cryptosporidial drugs.

Researchers focused on inhibiting lysyl-tRNA synthetase (KRS), an enzyme essential for parasite survival. By profiling a diverse set of potent KRS inhibitors, they aimed to identify the optimal physicochemical and pharmacokinetic properties required to reach the parasite in a mouse infection model. Fourteen compounds were selected based on their solubility and permeability characteristics.

Compounds with either restricted solubility or restricted permeability demonstrated the highest reduction of parasite shedding in mice. Two compounds (DDD489 and DDD508) were identified as the most effective, achieving over 99.8% parasite reduction without a relapse or recrudescence.

Both compounds also reduced parasites in a calf model, with treated calves showing significantly reduced diarrhea severity compared to control groups.

DDD489 and DDD508 have been selected for progression to preclinical safety studies, expanding the potential treatment options for cryptosporidiosis.

These findings provide a guide for the physicochemical and pharmacokinetic properties required for an effective cryptosporidiosis treatment. Advancing these compounds to preclinical safety studies is the first step in developing a treatment for this neglected infectious disease.

More information: Nicola Caldwell et al, Cryptosporidium lysyl-tRNA synthetase inhibitors define the interplay between solubility and permeability required to achieve efficacy, Science Translational Medicine (2024). DOI: 10.1126/scitranslmed.adm8631

Journal information:Science Translational Medicine

© 2024 Science X Network

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