Identification and Validation of Small-Gatekeeper Kinases as Drug Targets in Giardia lamblia

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Abstract

Author Summary The eukaryotic protozoan Giardia lamblia is the most commonly reported intestinal parasite worldwide. Current treatments used to treat giardiasis include metronidazole and other nitroimidazole derivatives. However, emergence of metronidazole-resistance strains and adverse reactions to the treatments suggest that alternative therapies against giardiasis are necessary. Here we identify a set of protein kinases in the Giardia genome that have an atypically small amino acid residue, called the gatekeeper residue, in the ATP binding pocket. Small gatekeeper residues are rare in mammalian kinases. We investigated whether this subset of kinases is necessary for parasite growth and proliferation and, if so, could they be targeted with a class of compounds called bumped kinase inhibitors (BKIs), designed to exploit the enlarged active site pocket made accessible by the small gatekeeper amino acid. Morpholino knockdown of two of the small gatekeeper kinases produced a distinctive phenotype characterized by defective cytokinesis. This phenotype was mimicked in Giardia cells treated with our most potent BKI. These results suggest that BKIs may be developed to selectively target small gatekeeper kinases in Giardia lamblia to provide a novel treatment option for giardiasis.

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Hennessey, K. M., Smith, T. R., Xu, J. W., Alas, G. C. M., Ojo, K. K., Merritt, E. A., & Paredez, A. R. (2016). Identification and Validation of Small-Gatekeeper Kinases as Drug Targets in Giardia lamblia. PLoS Neglected Tropical Diseases, 10(11). https://doi.org/10.1371/journal.pntd.0005107

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