title: A novel protein kinase is essential in bloodstream Trypanosoma brucei.
abstract: Human African trypanosomiasis a fatal disease for which no vaccines exist and treatment regimens are difficult. Here, we evaluate a Trypanosoma brucei protein kinase, AEK1, as a potential drug target. Conditional knockouts confirmed AEK1 essentiality in bloodstream forms. For chemical validation, we overcame the lack of AEK1 inhibitors by creating parasites expressing a single, functional analog-sensitive AEK1 allele. Analog treatment of mice infected with this strain delayed parasitemia and death, with one-third of animals showing no parasitemia. These studies validate AEK1 as a drug target and highlight the need for further understanding of its function.
authors.affiliation: Center for Infectious Disease Research, formerly Seattle Biomedical Research Institute, 307 Westlake Ave. N., Seattle, WA 98109, USA.
authors.forename: Bryan C
authors.initials: BC
authors.lastname: Jensen
authors.affiliation: Center for Infectious Disease Research, formerly Seattle Biomedical Research Institute, 307 Westlake Ave. N., Seattle, WA 98109, USA.
authors.forename: Nick
authors.initials: N
authors.lastname: Booster
authors.affiliation: Dept. of Chemistry, University of Washington, Seattle, WA 98195, USA.
authors.forename: Rama Subba Rao
authors.initials: RS
authors.lastname: Vidadala
authors.affiliation: Dept. of Chemistry, University of Washington, Seattle, WA 98195, USA; Dept. of Biochemistry, University of Washington, Seattle, WA 98195, USA.
authors.forename: Dustin J
authors.initials: DJ
authors.lastname: Maly
authors.affiliation: Center for Infectious Disease Research, formerly Seattle Biomedical Research Institute, 307 Westlake Ave. N., Seattle, WA 98109, USA; Dept. of Global Health, University of Washington, Seattle, WA 98195, USA. Electronic address: marilyn.parsons@cidresearch.org.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Parsons
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000483:Alleles; D000818:Animals; D055786:Gene Knockout Techniques; D006801:Humans; D051379:Mice; D018512:Parasitemia / Q000097:blood / Q000188:drug therapy / Q000469:parasitology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D014344:Trypanocidal Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D014353:Trypanosomiasis, African / Q000097:blood / Q000188:drug therapy / Q000469:parasitology*
chemical_list: D047428:Protein Kinase Inhibitors; D014344:Trypanocidal Agents; D000255:Adenosine Triphosphate; D011494:Protein Kinases
keywords: AGC kinase; Analog-sensitive; Drug target; In vivo; Protein kinase; Trypanosome