Cryptosporidium spp. and Toxoplasma gondii are also Category B biothreat agents because their infectious forms resist chemical inactivation and can be easily harvested and introduced into food and water supplies. Cryptosporidium are a major cause of prolonged and disabling diarrhea and Toxoplasma can cause a serious illness upon primary infection that is particularly dangerous to pregnant women. There is only one FDA- approved drug for cryptosporidiosis, and its efficacy is controversial. Therapeutic options for Toxoplasma are limited by toxicity. The C. parvum and T. gondii calcium dependent protein kinase 1 (Cp &TgCDPK1) can be selectively targeted with so-called Bumped Kinase Inhibitors (BKIs) that do not inhibit mammalian kinases, and these BKIs prevent the growth of cryptosporidium and toxoplasma. The BKIs have good oral bioavailability, pharmacokinetic, and are easy to synthesize. One of our lead BKIs has been shown to have efficacy in mouse models of cryptosporidiosis and toxoplasmosis. Thus BKIs are now excellent lead candidates for drug development for the therapy of cryptosporidiosis and toxoplasmosis. This proposal is to move the BKIs through pre-clinical development and select a clinical candidate. The goal of this project is to have a clinical candidate for the therapy of cryptosporidiosis and toxoplasmosis that is ready to undergo FDA IND review, with 1-2 compounds as backups.

Public Health Relevance

Cryptosporidium spp. are a major cause of prolonged disabling diarrhea, and there are only poorly efficacious drugs available now for Cryptosporidium treatment. Toxoplasma gondii causes disabling primary infection, and can endanger the fetus of pregnant women. Therapy for T. gondii is limited due to toxicity. This proposal is to test drug candidates, developed in another NIAID funded project, for cryptosporidiosis and toxoplasmosis to the point where they can be tested in humans. In the end, the goal is to have a drug candidate for regulatory (FDA) approval, with 1-2 compounds as backups.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-AWA-M (J2))
Program Officer
Rogers, Martin J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Washington
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Pedroni, Monica J; Vidadala, Rama Subba Rao; Choi, Ryan et al. (2016) Bumped kinase inhibitor prohibits egression in Babesia bovis. Vet Parasitol 215:22-8
Bansal, Abhisheka; Ojo, Kayode K; Mu, Jianbing et al. (2016) Reduced Activity of Mutant Calcium-Dependent Protein Kinase 1 Is Compensated in Plasmodium falciparum through the Action of Protein Kinase G. MBio 7:
Huang, Wenlin; Hulverson, Matthew A; Zhang, Zhongsheng et al. (2016) 5-Aminopyrazole-4-carboxamide analogues are selective inhibitors of Plasmodium falciparum microgametocyte exflagellation and potential malaria transmission blocking agents. Bioorg Med Chem Lett 26:5487-5491
Castellanos-Gonzalez, Alejandro; Sparks, Hayley; Nava, Samantha et al. (2016) A Novel Calcium-Dependent Kinase Inhibitor, Bumped Kinase Inhibitor 1517, Cures Cryptosporidiosis in Immunosuppressed Mice. J Infect Dis 214:1850-1855
Vidadala, Rama Subba Rao; Rivas, Kasey L; Ojo, Kayode K et al. (2016) Development of an Orally Available and Central Nervous System (CNS) Penetrant Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitor with Minimal Human Ether-a-go-go-Related Gene (hERG) Activity for the Treatment of Toxoplasmosis. J Med Chem 59:6531-46
Ojo, Kayode K; Dangoudoubiyam, Sriveny; Verma, Shiv K et al. (2016) Selective inhibition of Sarcocystis neurona calcium-dependent protein kinase 1 for equine protozoal myeloencephalitis therapy. Int J Parasitol 46:871-880
Schaefer, Deborah A; Betzer, Dana P; Smith, Kylie D et al. (2016) Novel Bumped Kinase Inhibitors Are Safe and Effective Therapeutics in the Calf Clinical Model for Cryptosporidiosis. J Infect Dis 214:1856-1864
Hines, Siddra A; Ramsay, Joshua D; Kappmeyer, Lowell S et al. (2015) Theileria equi isolates vary in susceptibility to imidocarb dipropionate but demonstrate uniform in vitro susceptibility to a bumped kinase inhibitor. Parasit Vectors 8:33