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.
|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|
|Müller, Joachim; Aguado-Martínez, Adriana; Balmer, Vreni et al. (2017) Two Novel Calcium-Dependent Protein Kinase 1 Inhibitors Interfere with Vertical Transmission in Mice Infected with Neospora caninum Tachyzoites. Antimicrob Agents Chemother 61:|
|Hulverson, Matthew A; Vinayak, Sumiti; Choi, Ryan et al. (2017) Bumped-Kinase Inhibitors for Cryptosporidiosis Therapy. J Infect Dis 215:1275-1284|
|Golkowski, Martin; Vidadala, Rama Subba Rao; Lombard, Chloe K et al. (2017) Kinobead and Single-Shot LC-MS Profiling Identifies Selective PKD Inhibitors. J Proteome Res 16:1216-1227|
|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|
|Huang, Wenlin; Choi, Ryan; Hulverson, Matthew A et al. (2017) 5-Aminopyrazole-4-Carboxamide-Based Compounds Prevent the Growth of Cryptosporidium parvum. Antimicrob Agents Chemother 61:|
|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|
|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|
|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|
|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|
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