title: Extended-spectrum antiprotozoal bumped kinase inhibitors: A review.
abstract: Many life-cycle processes in parasites are regulated by protein phosphorylation. Hence, disruption of essential protein kinase function has been explored for therapy of parasitic diseases. However, the difficulty of inhibiting parasite protein kinases to the exclusion of host orthologues poses a practical challenge. A possible path around this difficulty is the use of bumped kinase inhibitors for targeting calcium-dependent protein kinases that contain atypically small gatekeeper residues and are crucial for pathogenic apicomplexan parasites' survival and proliferation. In this article, we review efficacy against the kinase target, parasite growth in vitro, and in animal infection models, as well as the relevant pharmacokinetic and safety parameters of bumped kinase inhibitors.
authors.affiliation: Department of Medicine, Division of Allergy and Infectious Diseases, Center for Emerging and Reemerging Infectious Diseases (CERID), University of Washington, Seattle, WA 98109, USA; Department of Global Health, University of Washington, Seattle, WA 98195, USA. Electronic address: wesley@uw.edu.
authors.forename: Wesley C
authors.initials: WC
authors.lastname: Van Voorhis
authors.affiliation: Portland VA Medical Center, Portland, OR 97239, USA.
authors.forename: J Stone
authors.initials: JS
authors.lastname: Doggett
authors.affiliation: Department of Global Health, University of Washington, Seattle, WA 98195, USA; Center for Infectious Disease Research, Seattle, WA 98109, USA.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Parsons
authors.affiliation: Department of Medicine, Division of Allergy and Infectious Diseases, Center for Emerging and Reemerging Infectious Diseases (CERID), University of Washington, Seattle, WA 98109, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Hulverson
authors.affiliation: Department of Medicine, Division of Allergy and Infectious Diseases, Center for Emerging and Reemerging Infectious Diseases (CERID), University of Washington, Seattle, WA 98109, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Choi
authors.affiliation: Department of Medicine, Division of Allergy and Infectious Diseases, Center for Emerging and Reemerging Infectious Diseases (CERID), University of Washington, Seattle, WA 98109, USA.
authors.forename: Samuel L M
authors.initials: SLM
authors.lastname: Arnold
authors.affiliation: School of Animal and Comparative Biomedical Sciences, College of Agriculture and Life Sciences, University of Arizona, Tucson, AZ 85721, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Riggs
authors.affiliation: Institute of Parasitology, Vetsuisse Faculty, University of Bern, Berne, Switzerland.
authors.forename: Andrew
authors.initials: A
authors.lastname: Hemphill
authors.affiliation: Department of Veterinary Science, University of Kentucky, Lexington, KY 40546, USA.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Howe
authors.affiliation: Department of Veterinary Microbiology and Pathology, College of Veterinary Medicine, Washington State University, Pullman, WA 99164-7040, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Mealey
authors.affiliation: The National Institutes of Health, NIAID, DEA, 5601 Fishers Lane, Rockville, MD 20892, USA.
authors.forename: Audrey O T
authors.initials: AOT
authors.lastname: Lau
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
authors.forename: Ethan A
authors.initials: EA
authors.lastname: Merritt
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
authors.forename: Dustin J
authors.initials: DJ
authors.lastname: Maly
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
authors.forename: Erkang
authors.initials: E
authors.lastname: Fan
authors.affiliation: Department of Medicine, Division of Allergy and Infectious Diseases, Center for Emerging and Reemerging Infectious Diseases (CERID), University of Washington, Seattle, WA 98109, USA. Electronic address: ojo67kk@u.washington.edu.
authors.forename: Kayode K
authors.initials: KK
authors.lastname: Ojo
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016782:Apicomplexa / Q000187:drug effects* / Q000201:enzymology; D001562:Benzimidazoles / Q000737:chemistry; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011528:Protozoan Infections / Q000188:drug therapy* / Q000517:prevention & control; D011725:Pyridines / Q000737:chemistry
chemical_list: D000981:Antiprotozoal Agents; D001562:Benzimidazoles; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C000619660:imidazopyridine; D011505:Protein-Tyrosine Kinases
keywords: Bumped kinase inhibitors; Calcium-dependent protein kinase; Gatekeeper residue