Tyrosine Kinase Inhibitors Display Potent Activity against Cryptosporidium parvum

• DOI: 10.1128/spectrum.03874-22
• Publication Date: 2022-12-19T14:01:38Z
• Authors: Maria G. Nava; Félix Calderón; Elena Fernández; Lluis Ballell; Paul Bamborough; Sumiti Vinayak
• Keywords: Cryptosporidium parvum; Kinome; Nitazoxanide; Drug repositioning

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