Science - USA (2019-08-30)

(Antfer) #1

  1. L. N. Johnson, Protein kinase inhibitors: Contributions from
    structure to clinical compounds.Q. Rev. Biophys. 42 ,1– 40
    (2009). doi:10.1017/S0033583508004745; pmid: 19296866

  2. C. Doeriget al., Malaria: Targeting parasite and host cell
    kinomes.Biochim. Biophys. Acta 1804 , 604–612 (2010).
    doi:10.1016/j.bbapap.2009.10.009; pmid: 19840874

  3. Z. Zhou, X. D. Fu, Regulation of splicing by SR proteins and SR
    protein-specific kinases.Chromosoma 122 , 191–207 (2013).
    doi:10.1007/s00412-013-0407-z; pmid: 23525660

  4. S. Agarwalet al., Two nucleus-localized CDK-like kinases with
    crucial roles for malaria parasite erythrocytic replication are
    involved in phosphorylation of splicing factor.J. Cell. Biochem.
    112 , 1295–1310 (2011). doi:10.1002/jcb.23034;
    pmid: 21312235

  5. E. Talevich, A. Mirza, N. Kannan, Structural and evolutionary
    divergence of eukaryotic protein kinases in Apicomplexa.
    BMC Evol. Biol. 11 , 321 (2011). doi:10.1186/1471-2148-11-321;
    pmid: 22047078

  6. M. Schneideret al., Human PRP4 kinase is required for
    stable tri-snRNP association during spliceosomal B complex
    formation.Nat. Struct. Mol. Biol. 17 , 216–221 (2010).
    doi:10.1038/nsmb.1718; pmid: 20118938

  7. S. Kernet al., Inhibition of the SR protein-phosphorylating CLK
    kinases of Plasmodium falciparum impairs blood stage
    replication and malaria transmission.PLOS ONE 9 , e105732
    (2014). doi:10.1371/journal.pone.0105732; pmid: 25188378

  8. F. J. Gamoet al., Thousands of chemical starting points
    for antimalarial lead identification.Nature 465 , 305– 310
    (2010). doi:10.1038/nature09107; pmid: 20485427

  9. P. Dranchaket al., Profile of the GSK published protein kinase
    inhibitor set across ATP-dependent and-independent
    luciferases: Implications for reporter-gene assays.PLOS ONE
    8 ,e57888 (2013). doi:10.1371/journal.pone.0057888;
    pmid: 23505445

  10. R. Axel, Scents and sensibility: A molecular logic of olfactory
    perception (Nobel lecture).Angew. Chem. Int. Ed. 44 ,6110– 6127
    (2005). doi:10.1002/anie.200501726;pmid:16175526

  11. T. Spangenberget al., The open access malaria box: A drug
    discovery catalyst for neglected diseases.PLOS ONE 8 ,e62906
    (2013). doi:10.1371/journal.pone.0062906; pmid: 23798988

  12. Q. Gaoet al., Evaluation of cancer dependence and druggability
    of PRP4 kinase using cellular, biochemical, and structural
    approaches.J. Biol. Chem. 288 , 30125–30138 (2013).
    doi:10.1074/jbc.M113.473348; pmid: 24003220

  13. J. M. Fraileet al., USP39 Deubiquitinase Is Essential forKRAS
    Oncogene-driven Cancer.J. Biol. Chem. 292 , 4164– 4175
    (2017). doi:10.1074/jbc.M116.762757; pmid: 28154181

  14. H. Hadjivassiliou, O. S. Rosenberg, C. Guthrie, The crystal
    structure of S. cerevisiae Sad1, a catalytically inactive
    deubiquitinase that is broadly required for pre-mRNA splicing.
    RNA 20 , 656–669 (2014). doi:10.1261/rna.042838.113;
    pmid: 24681967

  15. O. V. Makarova, E. M. Makarov, R. Lührmann, The 65 and
    110 kDa SR-related proteins of the U4/U6.U5 tri-snRNP are
    essential for the assembly of mature spliceosomes.EMBO J.
    20 , 2553–2563 (2001). doi:10.1093/emboj/20.10.2553;
    pmid: 11350945

  16. R. Hui, M. El Bakkouri, L. D. Sibley, Designing selective
    inhibitors for calcium-dependent protein kinases in
    apicomplexans.Trends Pharmacol. Sci. 36 , 452–460 (2015).
    doi:10.1016/j.tips.2015.04.011; pmid: 26002073
    30. S. Louridoet al., Calcium-dependent protein kinase 1 is an
    essential regulator of exocytosis in Toxoplasma.Nature 465 ,
    359 – 362 (2010). doi: 10 .1038/nature09022; pmid: 20485436
    31. B. F. Kafsack, H. J. Painter, M. Llinás, New Agilent platform
    DNA microarrays for transcriptome analysis of Plasmodium
    falciparum and Plasmodium berghei for the malaria research
    community.Malar. J. 11 , 187 (2012). doi:10.1186/1475-2875-11-
    187; pmid: 22681930
    32. M. J. Gardneret al., Genome sequence of the human malaria
    parasite Plasmodium falciparum.Nature 419 , 498–511 (2002).
    doi:10.1038/nature01097; pmid: 12368864
    33. D. A. Fidock, P. J. Rosenthal, S. L. Croft, R. Brun, S. Nwaka,
    Antimalarial drug discovery: Efficacy models for compound
    screening.Nat. Rev. Drug Discov. 3 , 509–520 (2004).
    doi:10.1038/nrd1416; pmid: 15173840
    34. J. Swannet al., High-Throughput Luciferase-Based Assay for
    the Discovery of Therapeutics That Prevent Malaria.
    ACS Infect. Dis. 2 , 281–293 (2016). doi:10.1021/
    acsinfecdis.5b00143; pmid: 27275010
    35. N. M. Brancucci, I. Goldowitz, K. Buchholz, K. Werling, M. Marti,
    An assay to probe Plasmodium falciparum growth,
    transmission stage formation and early gametocyte
    development.Nat. Protoc. 10 , 1131–1142 (2015). doi:10.1038/
    nprot.2015.072; pmid: 26134953
    36. J. N. Burrowset al., New developments in anti-malarial target
    candidate and product profiles.Malar. J. 16 , 26 (2017).
    doi:10.1186/s12936-016-1675-x; pmid: 28086874
    37. R. Roskoski Jr., A historical overview of protein kinases and
    their targeted small molecule inhibitors.Pharmacol. Res. 100 ,
    1 – 23 (2015). doi:10.1016/j.phrs.2015.07.010; pmid: 26207888
    38. C. W. McNamaraet al., Targeting Plasmodium PI(4)K to
    eliminate malaria.Nature 504 , 248–253 (2013). doi:10.1038/
    nature12782; pmid: 24284631
    39. I. S. Lucet, A. Tobin, D. Drewry, A. F. Wilks, C. Doerig,
    Plasmodium kinases as targets for new-generation
    antimalarials.Future Med.Chem. 4 , 2295–2310 (2012).
    doi:10.4155/fmc.12.183; pmid: 23234552
    40. W. A. Guiguemdeet al., Chemical genetics of Plasmodium
    falciparum.Nature 465 , 311–315 (2010). doi:10.1038/
    nature09099; pmid: 20485428
    41. D. Plouffeet al., In silico activity profiling reveals the
    mechanism of action of antimalarials discovered in a high-
    throughput screen.Proc. Natl. Acad. Sci. U.S.A. 105 , 9059– 9064
    (2008). doi:10.1073/pnas.0802982105;pmid: 18579783
    42. M. Rottmannet al., Spiroindolones, a potent compound class
    for the treatment of malaria.Science 329 , 1175–1180 (2010).
    doi:10.1126/science.1193225; pmid: 20813948
    43. I. D. Goodyer, T. F. Taraschi, Plasmodium falciparum: A simple,
    rapid method for detecting parasite clones in microtiter plates.
    Exp. Parasitol. 86 , 158–160 (1997). doi:10.1006/
    expr.1997.4156; pmid: 9207746
    44. L. M. Sanzet al., P. falciparum in vitro killing rates allow to
    discriminate between different antimalarial mode-of-action.
    PLOS ONE 7 , e30949 (2012). doi:10.1371/journal.
    pone.0030949; pmid: 22383983
    ACKNOWLEDGMENTS
    We thank the Proteomics facility of LaCTAD (Laboratório Central de
    Tecnologias de Alto Desempenho em Ciências da Vida, UNICAMP,
    Campinas, Brazil); A. da Silva Santiago, A. M. Fala, and P. Zonzini
    Ramos for assistance with PRPF4B protein production; Aché


Laboratórios Farmacêuticos for provision of compound A; E. Peat
and D. Armstrong for the maintenance of the IBAHCM/Glasgow
University mosquito insectaries; the Scottish National Blood
Transfusion service for the provision of human blood and serum;
N. Emami (Stockholm University) for assistance with serum supplies;
P. Johnson (IBAHCM, University of Glasgow) for discussions on
GLMM; and R. Tewari for providing theP. bergheicDNA library.
Funding:Supported by an MRC Toxicology Unit program grant
(A.B.T., M.M.A.), MRC Developmental Gap Fund (A.S.-A.), Lord Kelvin
Adam Smith Fellowship (M.M.A.), GSK Open Lab Foundation
Award (A.S.-A.), joint MRC Toxicology Unit and MRC Unit the Gambia
PhD program (O.J.), and Daphne Jackson Fellowship (D.M.). A.P.W.,
M.M., M.M.A., K.C., N.V.S., and S.B.M. are supported by Wellcome
Centre for Integrative Parasitology Core support award WT104111AIA.
E.A.W. is supported by grants from the NIH (5R01AI090141 and
R01AI103058) and by grants from the Bill & Melinda Gates
Foundation (OPP1086217, OPP1141300) as well as by Medicines for
Malaria Venture (MMV). Drug WR99210 for selection of transgenic
parasites was a gift from Jacobus Pharmaceuticals. M.M. is supported
through WT award 172862-01 and a Wolfson Merit award from the
Royal Society. The Structural Genomics Consortium (SGC) is a
registered charity (number 1097737) that receives funds from AbbVie,
Bayer Pharma AG, Boehringer Ingelheim, the Canada Foundation for
Innovation, the Eshelman Institute for Innovation, Genome Canada,
the Innovative Medicines Initiative (European Union [EU]/European
Federation of Pharmaceutical Industries and Associations [EFPIA])
(ULTRA-DD grant no. 115766), Janssen, Merck & Company, Merck
KGaA, Novartis Pharma AG, the Ontario Ministry of Economic
Development and Innovation, Pfizer, the São Paulo Research
Foundation (FAPESP number 2013/50724-5), Takeda, and the
Wellcome Trust (106169/ZZ14/Z). E.F.A. was supported by the
Tres Cantos Lab Foundation (grant TC125). A.B.C. was supported
by a Scottish Funding Council Global Challenges Research Fund
award to L.C.R.-C.Author contributions:A.B.T. conceived the
project, designed experiments, analyzed data, and was the
primary author; M.M.A., A.S.-A., O.J., and L.C.R.-C. designed
experiments, conducted experiments, analyzed data, and
contributed to writing; E.L.F., A.M., K.M., A.B.C., D.S., N.M.B.B.,
S.B.M., Y.A.K., N.V.S., J.A., D.M., L.S., K.D., C.J., C.Z., M.J.V.,
M.J.L.-M., and M.L.L. conducted experiments; G.C. and K.C.
conducted data analysis; P.H.C.G., J.M.E., D.C., D.C.N., A.P.W.,
A.G.J., E.F.A., M.M., E.A.W., and F.J.G. contributed to experimental
design and to writing the manuscript.Competing interests:The
authors declare no conflicts of interest.Data and materials
availability:The GSK compounds were obtained under a materials
transfer agreement from GSK. All other data are available in the
manuscript or the supplementary materials. Some of the data in this
manuscript have been deposited atwww.biorxiv.org/content/
10.1101/404459v1.article-info.

SUPPLEMENTARY MATERIALS
science.sciencemag.org/content/365/6456/eaau1682/suppl/DC1
Materials and Methods
Figs. S1 to S13
Tables S1 to S5
References ( 45 – 51 )
11 July 2018; resubmitted 15 March 2019
Accepted 12 July 2019
10.1126/science.aau1682

Alamet al.,Science 365 , eaau1682 (2019) 30 August 2019 8of8


RESEARCH | RESEARCH ARTICLE

Free download pdf