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AEE788 Inhibits Basal Body Assembly and Blocks DNA Replication in the African Trypanosome S

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AEE788 Inhibits Basal Body Assembly and Blocks DNA Replication in the African Trypanosome S Supplemental material to this article can be found at: http://molpharm.aspetjournals.org/content/suppl/2017/03/10/mol.116.106906.DC2 1521-0111/91/5/482–498$25.00 https://doi.org/10.1124/mol.116.106906 MOLECULAR PHARMACOLOGY Mol Pharmacol 91:482–498, May 2017 Copyright ª 2017 by The American Society for Pharmacology and Experimental Therapeutics AEE788 Inhibits Basal Body Assembly and Blocks DNA Replication in the African Trypanosome s Catherine Sullenberger, Daniel Piqué, Yuko Ogata, and Kojo Mensa-Wilmot Department of Cellular Biology, and Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, Georgia (C.S., D.P., K.M.-W.); and the Proteomics Facility, Fred Hutchinson Cancer Research Center, Seattle, Washington (Y.O.) Received September 10, 2016; accepted February 17, 2017 ABSTRACT Downloaded from Trypanosoma brucei causes human African trypanosomiasis following: 1) basal body and bilobe duplication are concurrent; (HAT). The pyrrolopyrimidine AEE788 (a hit for anti-HAT drug 2) maturation of probasal bodies, marked by TbRP2 recruit- discovery) associates with three trypanosome protein ki- ment, is coupled with nascent basal body assembly, moni- nases. Herein we delineate the effects of AEE788 on T. brucei tored by localization of TbSAS6 at newly forming basal bodies; using chemical biology strategies. AEE788 treatment inhibits and 3) kinetoplast division is observed in G2 after completion DNA replication in the kinetoplast (mitochondrial nucleoid) of nuclear DNA synthesis. Prolonged exposure of trypano- and nucleus. In addition, AEE788 blocks duplication of the somes to AEE788 inhibited transferrin endocytosis, altered molpharm.aspetjournals.org basal body and the bilobe without affecting mitosis. Thus, cell morphology, and decreased cell viability. To discover AEE788 prevents entry into the S-phase of the cell division putative effectors for the pleiotropic effects of AEE788, cycle. To study the kinetics of early events in trypanosome proteome-wide changes in protein phosphorylation induced division, we employed an “AEE788 block and release” pro- by the drug were determined. Putative effectors include an SR tocol to stage entry into the S-phase. A time-course of DNA protein kinase, bilobe proteins, TbSAS4, TbRP2, and BILBO- synthesis (nuclear and kinetoplast DNA), duplication of or- 1. Loss of function of one or more of these effectors can, from ganelles (basal body, bilobe, kinetoplast, nucleus), and cyto- published literature, explain the polypharmacology of AEE788 kinesis was obtained. Unexpected findings include the on trypanosome biology. at ASPET Journals on October 1, 2021 Introduction Subsequently, AEE788 was established as an anti-trypanosomal lead drug (Behera et al., 2014). AEE788 forms complexes Trypanosoma brucei is a protozoan parasite that causes with three trypanosome protein kinases (Katiyar et al., human African trypanosomiasis (HAT) (reviewed by Lejon 2013), suggesting that it is a multitargeted antagonist or and Büscher, 2005; Kennedy, 2013). Current HAT chemother- agonist (Dar and Shokat, 2011) whose toxicity to trypano- apies are administered by injection and have toxic side effects somes is likely based on exerting pleiotropic biologic effects. (for review, see Babokhov et al., 2013), making them far from Stages of the trypanosome cell division cycle can be ideal. An attractive drug discovery approach for neglected identified by enumeration of single-copy organelles, including tropical diseases, such as HAT, is chemical scaffold repurpos- the kinetoplast [mitochondrial nucleoid containing kineto- ing (Patel et al., 2013). In this strategy, drugs with proven plast DNA (kDNA)], basal body, and nucleus (Sherwin and efficacy against other diseases are screened for activity Gull, 1989; Woodward and Gull, 1990). In G1, trypanosomes against HAT, reducing the time and cost associated with have a single round kinetoplast and a single nucleus (1K1N) early-stage drug discovery (DiMasi et al., 2003). We identified (Sherwin and Gull, 1989). As cells transition into the S-phase, a small-molecule kinase inhibitor, AEE788 (Traxler et al., synthesis of kDNA (for review, see Jensen and Englund, 2012) 2004; Meco et al., 2010), as a “hit” (growth inhibitory is associated with kinetoplast elongation (Gluenz et al., 2011), concentration by 50% 5 2.5 mM) for HAT drug discovery. generating early S-phase cells with a single elongated kinet- oplast (Ke) and one nucleus (1Ke1N) (Siegel et al., 2008). This work was funded by the National Institutes of Health [Grant Division of the kinetoplast precedes mitosis forming a 2K1N R01AI124046]. population (Woodward and Gull, 1990). Mitosis produces https://doi.org/10.1124/mol.116.106906. s This article has supplemental material available at molpharm. 2K2N trypanosomes, which become two 1K1N cells after aspetjournals.org. cytokinesis (Sherwin and Gull, 1989), completing the division ABBREVIATIONS: 1K1N, single nucleus in kinetoplast; 1Ke1N, one nucleus in elongated kinetoplast; BSA, bovine serum albumin; CCD, charge- coupled device; DAPI, 49,6-diamidino-2-phenylindole; DMSO, dimethylsulfoxide; EdU, 5-ethynyl-29-deoxyuridine; FAZ, flagellar attachment zone; HAT, human African trypanosomiasis; IMAC, immobilized-metal affinity chromatography; kDNA, kinetoplast DNA; Ke, elongated kinetoplast; LC- MS/MS, liquid chromatography tandem mass spectrometry; mBB, mature basal body; pBB, probasal body; PBS, phosphate-buffered saline; PBSG, phosphate-buffered saline with 1% glucose; PFA, paraformaldehyde; PFR, paraflagellar rod; PI, propidium iodide; PIC, phosphatase inhibitor cocktail; Tf, transferrin; TFA, trifluoroacetic acid; TL, tomato lectin; T10, time at which 10% of the observed maximum is reached; T50, time at which 50% of the observed maximum is reached; T90, time at which 90% of the observed maximum is reached. 482 Chemical Biology of AEE788 in the African Trypanosome 483 cycle (for review, see Hammarton, 2007; Li, 2012; Zhou et al., were incubated at 37°C in 5% CO2. Trypanosome density was 2014). measured with a hemocytometer after 4, 9, and 16 hours of incubation. The basal body is the microtubule-organizing center for the Both sides of the hemocytometer were counted twice and averaged for flagellar axoneme. Additionally, the basal body is attached to every time point. Biologic replicates were performed twice. 9 the kinetoplast (Ogbadoyi et al., 2003) and has a role in 4 ,6-Diamidino-2-Phenylindole Staining of DNA in the Kinetoplast and Nucleus After AEE788 Treatment. T. brucei inheritance of the mitochondrial genome (Robinson and Gull, (5 Â 105 cells/ml) was treated with AEE788 (5 mM), or an equal volume 1991). Accordingly, basal body biogenesis is tightly coordi- (0.1%) of DMSO (drug solvent) for 4 hours at 37°C in 5% CO2. Treated nated with the cell division cycle (Sherwin and Gull, 1989; cells were pelleted (3000g for 5 minutes), resuspended in 1 ml of 4% Woodward and Gull, 1990; Gluenz et al., 2011). Prior to paraformaldehyde (PFA) (Affymetrix, Santa Clara, CA) in phosphate- duplication, trypanosomes have a mature basal body (mBB) buffered saline (PBS) (Thermo Fisher), and incubated for 15 minutes adjacent to an immature probasal body (pBB) (Sherwin and at room temperature. Cells were pelleted by centrifugation, as Gull, 1989). Maturation of the pBB produces cells with two described previously, and adhered to poly-L-lysine (Sigma-Aldrich, mBBs, each of which seed a new pBB (Sherwin and Gull, 1989; St. Louis, MO)–coated coverslips for 15 minutes. Coverslips were Lacomble et al., 2010; Gluenz et al., 2011). No quantitative briefly washed with PBS before being mounted onto microscope slides time-course study of the conversion of putative intermediates with VectaShield Mounting Medium (Vector Laboratories, Burlingame, CA), containing 1.5 mM49,6-diamidino-2-phenylindole (DAPI) to stain into mBBs has been reported. nuclear and kinetoplast DNA. Trypanosomes were visualized with a The flagellum exits the trypanosome cell body via the high-sensitivity interline camera on an EVOS fluorescence (EVOS FL) Downloaded from flagellar pocket (Lacomble et al., 2009). Duplication of the microscope (Life Technologies, Grand Island, NY). The number of flagellar pocket depends on basal body duplication and kinetoplasts and nuclei per cell, in 150 trypanosomes, were scored in separation (Lacomble et al., 2010). Outside the cell body, the four independent experiments. flagellar membrane is conjoined to the plasma membrane by Time-Course for Duplication of the Kinetoplast and Nu- the flagellar attachment zone (FAZ) (Sherwin and Gull, 1989; cleus. After a 4-hour treatment with AEE788 (5 mM), trypanosomes Kohl et al., 1999). Cytokinesis requires duplication of the were washed twice and resuspended in drug-free HMI-9 medium (5 Â 5 molpharm.aspetjournals.org flagellum and its associated cytoskeletal structures (Robinson 10 cells/ml). Cells were returned to an incubator (37°C, 5% CO2) for 1, et al., 1995; Kohl et al., 2003). The bilobe is a cytoskeletal 2, 3, 4, 5, or 6 hours. Cells were fixed and stained with DAPI as structure closely associated with the FAZ filament (Esson described above. Trypanosomes (150) were scored based on their number of kinetoplasts and nuclei (n 5 3 for each time point). et al., 2012) and is implicated in FAZ formation (Zhou et al., Detection of DNA Synthesis with 5-Ethynyl-29-Deoxyuri- 2010; Bangs, 2011). The flagellar pocket is the major site of dine. Bloodstream trypanosomes (5 Â 105 cells/ml) were treated with endocytosis, a process needed for nutrient
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