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.
|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|
|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|
|MÃ¼ller, Joachim; Hemphill, Andrew (2016) Drug target identification in protozoan parasites. Expert Opin Drug Discov 11:815-24|
|Winzer, Pablo; MÃ¼ller, Joachim; Aguado-MartÃnez, Adriana et al. (2015) In Vitro and In Vivo Effects of the Bumped Kinase Inhibitor 1294 in the Related Cyst-Forming Apicomplexans Toxoplasma gondii and Neospora caninum. Antimicrob Agents Chemother 59:6361-74|
|Doggett, J Stone; Ojo, Kayode K; Fan, Erkang et al. (2014) Bumped kinase inhibitor 1294 treats established Toxoplasma gondii infection. Antimicrob Agents Chemother 58:3547-9|