Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI111341-04
Application #
9233010
Study Section
Special Emphasis Panel (ZAI1-AWA-M (J2))
Program Officer
O'Neil, Michael T
Project Start
2014-03-15
Project End
2019-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
4
Fiscal Year
2017
Total Cost
$1,230,645
Indirect Cost
$351,277

  Institution

Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195

  Publications

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
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
Müller, Joachim; Aguado-Martínez, Adriana; Ortega-Mora, Luis-Miguel et al. (2017) Development of a murine vertical transmission model for Toxoplasma gondii oocyst infection and studies on the efficacy of bumped kinase inhibitor (BKI)-1294 and the naphthoquinone buparvaquone against congenital toxoplasmosis. J Antimicrob Chemother 72:2334-2341
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:
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:
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

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