Tyrosine Kinase Inhibitors Display Potent Activity against Cryptosporidium parvum

Abstract

ABSTRACT The protozoan parasite Cryptosporidium is a leading cause of diarrheal disease (cryptosporidiosis) and death in young children. Cryptosporidiosis can be life-threatening in individuals with weak immunity such as HIV/AIDS patients and organ transplant recipients. There is currently no effective drug to treat cryptosporidiosis in the pediatric and immunocompromised population. Therefore, there is an urgent need to expedite the drug discovery process in order to develop new and effective therapies to reduce the global disease burden of cryptosporidiosis. In this study, we employed a drug repurposing strategy to screen a library of 473 human kinase inhibitors to determine their activity against Cryptosporidium parvum. We have identified 67 new anti-cryptosporidial compounds using phenotypic screening based on a transgenic C. parvum strain expressing a luciferase reporter. Further, dose-response assays led to the identification of 11 hit compounds that showed potent inhibition of C. parvum at nanomolar concentration. Kinome profiling of these 11 prioritized hits identified compounds that displayed selectivity in targeting specific families of kinases, particularly tyrosine kinases. Overall, this study identified tyrosine kinase inhibitors that hold potential for future development as new drug candidates against cryptosporidiosis. IMPORTANCE The intestinal parasite Cryptosporidium parvum is a major cause of diarrhea-associated morbidity and mortality in children, immunocompromised people, and young ruminant animals. With no effective drug available to treat cryptosporidiosis in humans and animals, there is an urgent need to identify anti-parasitic compounds and new targets for drug development. To address this unmet need, we screened a GSK library of kinase inhibitors and identified several potent compounds, including tyrosine kinase inhibitors, that were highly effective in killing C. parvum. Overall, our study revealed several novel compounds and a new family of kinases that can be targeted for anti-cryptosporidial drug development.

Keywords

• Cryptosporidium
• anti-parasitic compounds
• cryptosporidiosis
• kinase library screening
• protozoan parasite
• tyrosine kinase inhibitors