New drugs are urgently needed for cryptosporidiosis and toxoplasmosis for human and domestic livestock use. Cryptosporidiosis causes wasting diarrhea in humans and calves. Toxoplasmosis is an important cause of fetal malformations and abortions in humans and domestic livestock. In addition, an effective drug is also needed for veterinary use for neosporosis, the cause of epidemic abortions in livestock. This project follows on our successful hit-to-lead drug development project, targeting protozoan Calcium Dependent Protein Kinases (CDPKs). We now have two promising pre-clinical drug candidates that show activity in mouse models of cryptosporidiosis, toxoplasmosis and neosporosis, and thus are of great potential value for both veterinary and human health. The goal of this project will be to conduct efficacy, pharmacokinetic (PK), and toxicity testing of our novel therapeutics in agriculturally-important domestic animals (cattle and sheep) to show efficacy for animal diseases and to also gather information for the preclinical drug package for human use. We will scale-up the compounds to the near kilogram quantity, test their efficacy in sheep models of toxoplasmosis and neosporosis, and in a calf model of cryptosporidiosis. In the end of this project, the goal is to have a preclinical drug candidate and one or two backups to advance to final preclinical testing and IND/NADA registration for veterinary and human use.
Cryptosporidium spp are a major cause of prolonged disabling diarrhea both in newborn farm animals and children up to 2 years old, and there are no efficacious drugs available now for Cryptosporidium treatment. Toxoplasma gondii causes disabling primary infection, and can endanger the fetus of pregnant women and farm animals and Neospora caninum causes epidemic abortion in cattle and over $1.2 billion in world-wide economic losses to the cattle industry. This proposal is to test drug candidates, developed in another NIAID funded project, for cryptosporidiosis, toxoplasmosis, and neosporosis to the point where they can be developed as a dual therapy for human and farm animal use.
| Lee, Sangun; Ginese, Melanie; Beamer, Gillian et al. (2018) Therapeutic Efficacy of Bumped Kinase Inhibitor 1369 in a Pig Model of Acute Diarrhea Caused by Cryptosporidium hominis. Antimicrob Agents Chemother 62: |
| Hennessey, Kelly M; Rogiers, Ilse C; Shih, Han-Wei et al. (2018) Screening of the Pathogen Box for inhibitors with dual efficacy against Giardia lamblia and Cryptosporidium parvum. PLoS Negl Trop Dis 12:e0006673 |
| Scheele, Suzanne; Geiger, Jennifer A; DeRocher, Amy E et al. (2018) Toxoplasma Calcium-Dependent Protein Kinase 1 Inhibitors: Probing Activity and Resistance Using Cellular Thermal Shift Assays. Antimicrob Agents Chemother 62: |
| Sánchez-Sánchez, Roberto; Ferre, Ignacio; Re, Michela et al. (2018) Safety and efficacy of the bumped kinase inhibitor BKI-1553 in pregnant sheep experimentally infected with Neospora caninum tachyzoites. Int J Parasitol Drugs Drug Resist 8:112-124 |
| Gimenez, Fernanda; Hines, Siddra A; Evanoff, Ryan et al. (2018) In vitro growth inhibition of Theileria equi by bumped kinase inhibitors. Vet Parasitol 251:90-94 |
| Hulverson, Matthew A; Vinayak, Sumiti; Choi, Ryan et al. (2017) Bumped-Kinase Inhibitors for Cryptosporidiosis Therapy. J Infect Dis 215:1275-1284 |
| Arnold, Samuel L M; Choi, Ryan; Hulverson, Matthew A et al. (2017) Necessity of Bumped Kinase Inhibitor Gastrointestinal Exposure in Treating Cryptosporidium Infection. J Infect Dis 216:55-63 |
| Hulverson, Matthew A; Choi, Ryan; Arnold, Samuel L M et al. (2017) Advances in bumped kinase inhibitors for human and animal therapy for cryptosporidiosis. Int J Parasitol 47:753-763 |
| Van Voorhis, Wesley C; Doggett, J Stone; Parsons, Marilyn et al. (2017) Extended-spectrum antiprotozoal bumped kinase inhibitors: A review. Exp Parasitol 180:71-83 |
| Jiménez-Meléndez, Alejandro; Ojo, Kayode K; Wallace, Alexandra M et al. (2017) In vitro efficacy of bumped kinase inhibitors against Besnoitia besnoiti tachyzoites. Int J Parasitol 47:811-821 |
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