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.
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.
| Golkowski, Martin; Perera, Gayani K; Vidadala, Venkata Narayana et al. (2018) Kinome chemoproteomics characterization of pyrrolo[3,4-c]pyrazoles as potent and selective inhibitors of glycogen synthase kinase 3. Mol Omics 14:26-36 |
| 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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