New therapeutics are needed for infections caused by the intestinal parasite Giardia. Current approved drugs have limiting toxicity and are ineffective dur to resistance in up to 20% of cases. We have identified a set of protein kinases in the Giardia genome that share an unusual structure feature in their active site. This feature, an atypically small gatekeeper residue, confers sensitivity to a class of compounds called bumped kinase inhibitors (BKI) that do not inhibit mammalian kinases. BKIs in general show good pharmacological properties and have shown minimal toxicity in mice when administered in the course of other work. We have demonstrated in preliminary work that even incomplete knockdown of these small-gatekeeper kinases significantly impairs Giardia growth. We have also shown that BKIs are active against Giardia in culture. We will use genetic and chemical probes to rigorously validate these kinases as drug targets. We will confirm that BKIs found to be active in suppressing Giardia growth, cell attachment, or encystation act by inhibiting specific kinases. A primary goal is to use SAR-guided synthetic chemistry to develop compounds that are orally bioavailable, sufficiently potent, lack toxicity, and cure animal models of Giardia infection. By the end of this project we expect to have lead compounds for evaluation as potential drugs against giardiasis.

Public Health Relevance

This project will initiate discovery and development of new drugs to giardiasis, a disease caused by parasitic protozoa commonly transmitted by contaminated food or unpurified water. We have identified a class of chemical compounds that act on certain atypical proteins found in the Giardia genome. We will design and characterize compounds of this class that are nontoxic to humans but effective in treating Giardia infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI127493-02
Application #
9390030
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
O'Neil, Michael T
Project Start
2016-12-01
Project End
2019-11-30
Budget Start
2017-12-01
Budget End
2019-11-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Washington
Department
Biochemistry
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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
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
Hennessey, Kelly M; Smith, Tess R; Xu, Jennifer W et al. (2016) Identification and Validation of Small-Gatekeeper Kinases as Drug Targets in Giardia lamblia. PLoS Negl Trop Dis 10:e0005107