Hostname: page-component-8448b6f56d-c4f8m Total loading time: 0 Render date: 2024-04-23T09:43:35.882Z Has data issue: false hasContentIssue false
  • English
  • Français

N-Myristoyltransferase as a potential drug target in malaria and leishmaniasis

Published online by Cambridge University Press:  24 April 2013

EDWARD W. TATE ,
ANDREW S. BELL ,
MARK D. RACKHAM  and
MEGAN H. WRIGHT
EDWARD W. TATE*
Affiliation:
Department of Chemistry, Institute of Chemical Biology, Imperial College London, London SW7 2AZ, UK
ANDREW S. BELL
Affiliation:
Department of Chemistry, Institute of Chemical Biology, Imperial College London, London SW7 2AZ, UK
MARK D. RACKHAM
Affiliation:
Department of Chemistry, Institute of Chemical Biology, Imperial College London, London SW7 2AZ, UK
MEGAN H. WRIGHT
Affiliation:
Department of Chemistry, Institute of Chemical Biology, Imperial College London, London SW7 2AZ, UK
*
*Corresponding author: Department of Chemistry, Institute of Chemical Biology, Imperial College London, London SW7 2AZ, UK. Tel: 020 7594 3752. Fax: 020 7594 1139. E-mail e.tate@imperial.ac.uk
Get access Rights & Permissions [Opens in a new window]

Summary

Infections caused by protozoan parasites are among the most widespread and intractable transmissible diseases affecting the developing world, with malaria and leishmaniasis being the most costly in terms of morbidity and mortality. Although new drugs are urgently required against both diseases in the face of ever-rising resistance to frontline therapies, very few candidates passing through development pipelines possess a known and novel mode of action. Set in the context of drugs currently in use and under development, we present the evidence for N-myristoyltransferase (NMT), an enzyme that N-terminally lipidates a wide range of specific target proteins through post-translational modification, as a potential drug target in malaria and the leishmaniases. We discuss the limitations of current knowledge regarding the downstream targets of this enzyme in protozoa, and our recent progress towards potent cell-active NMT inhibitors against the most clinically-relevant species of parasite. Finally, we outline the next steps required in terms of both tools to understand N-myristoylation in protozoan parasites, and the generation of potential development candidates based on the output of our recently-reported high-throughput screens.

Keywords

Malarialeishmaniasismedicinal chemistrychemical biologyPlasmodium vivaxLeishmania donovaniPlasmodium falciparumhigh-throughput screening
Type
Research Article
Information
Parasitology , Volume 141 , Issue 1: Symposia of the British Society for Parasitology volume 49 Emerging paradigms in anti-infective drug design , January 2014 , pp. 37 - 49
Copyright
Copyright © Cambridge University Press 2013 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

Arevalo, I., Ward, B., Miller, R., Meng, T.-C., Najar, E., Alvarez, E., Matlashewski, G. and Alejandro, L.-C. (2001). Successful treatment of drug-resistant cutaneous leishmaniasis in humans by use of imiquimod, an immunomodulator. Clinical Infectious Diseases 33, 1847–1851.Google Scholar
Baum, J., Richard, D., Healer, J., Rug, M., Krnajski, Z., Gilberger, T. W., Green, J. L., Holder, A. A. and Cowman, A. F. (2006). A conserved molecular motor drives cell invasion and gliding motility across malaria life cycle stages and other apicomplexan parasites. Journal of Biological Chemistry 281, 5197–5208.CrossRefGoogle ScholarPubMed
Bell, A. S., Mills, J. E., Williams, G. P., Brannigan, J. A., Wilkinson, A. J., Parkinson, T., Leatherbarrow, R. J., Tate, E. W., Holder, A. A. and Smith, D. F. (2012). Selective inhibitors of protozoan protein N-myristoyltransferases as starting points for tropical disease medicinal chemistry programs. PLoS Neglected Tropical Diseases 6, e1625.Google Scholar
Bembenek, S. D., Tounge, B. A. and Reynolds, C. H. (2009). Ligand efficiency and fragment-based drug discovery. Drug Discovery Today 14, 278–283.CrossRefGoogle ScholarPubMed
Bhatnagar, R. S., Futterer, K., Farazi, T. A., Korolev, S., Murray, C. L., Jackson-Machelski, E., Gokel, G. W., Gordon, J. I. and Waksman, G. (1998). Structure of N-myristoyltransferase with bound myristoylCoA and peptide substrate analogs. Nature Structural Biology 5, 1091–1097.CrossRefGoogle ScholarPubMed
Billker, O., Dechamps, S., Tewari, R., Wenig, G., Franke-Fayard, B. and Brinkmann, V. (2004). Calcium and a calcium-dependent protein kinase regulate gamete formation and mosquito transmission in a malaria parasite. Cell 117, 503–514.Google Scholar
Boisson, B., Giglione, C. and Meinnel, T. (2003). Unexpected protein families including cell defense components feature in the N-myristoylome of a higher eukaryote. Journal of Biological Chemistry 278, 43418–43429.Google Scholar
Bologna, G., Yvon, C., Duvaud, S. and Veuthey, A. L. (2004). N-Terminal myristoylation predictions by ensembles of neural networks. Proteomics 4, 1626–1632.Google Scholar
Botté, C. Y., Dubar, F., McFadden, G. I., Maréchal, E. and Biot, C. (2012). Plasmodium falciparum apicoplast drugs: targets or off-targets? Chemical Reviews 112, 1269–1283.CrossRefGoogle ScholarPubMed
Bowyer, P. W., Gunaratne, R. S., Grainger, M., Withers-Martinez, W., Wickramsinghe, S. R., Tate, E. W., Leatherbarrow, R. J., Brown, K. A., Holder, A. A. and Smith, D. F. (2007). Molecules incorporating a benzothiazole core scaffold inhibit the N-myristoyltransferase of Plasmodium falciparum. Biochemical Journal 408, 173–180.Google Scholar
Bowyer, P. W., Tate, E. W., Leatherbarrow, R. J., Holder, A. A., Smith, D. F. and Brown, K. A. (2008). N-myristoyltransferase: a prospective drug target for protozoan parasites. ChemMedChem 3, 402–408.Google Scholar
Brannigan, J. A., Smith, B. A., Yu, Z., Brzozowski, A. M., Hodgkinson, M. R., Maroof, A., Price, H. P., Meier, F., Leatherbarrow, R. J., Tate, E. W., Smith, D. F. and Wilkinson, A. J. (2010). N-myristoyltransferase from Leishmania donovani: structural and functional characterisation of a potential drug target for visceral leishmaniasis. Journal of Molecular Biology 396, 985–999.CrossRefGoogle ScholarPubMed
Cabrera, A., Herrmann, S., Warszta, D., Santos, J. M., John Peter, A. T., Kono, M., Debrouver, S., Jacobs, T., Spielmann, T., Ungermann, C., Soldati-Favre, D. and Gilberger, T. W. (2012). Dissection of minimal sequence requirements for rhoptry membrane targeting in the malaria parasite. Traffic 13, 1335–1350.Google Scholar
Charman, S. A., Arbe-Barnes, S., Bathurst, I. C., Brun, R., Campbell, M., Charman, W. N., Chiu, F. C. K., Chollet, J., Craft, J. C., Creek, D. J., Dong, Y., Matile, H., Maurer, M., Morizzi, J., Nguyen, T., Papastogiannidis, P., Scheurer, C., Shackleford, D. M., Sriraghavan, K., Stingelin, L., Tang, Y., Urwyler, H., Wang, X., White, K. L., Wittlin, S., Zhou, L. and Vennerstrom, J. L. (2011). Synthetic ozonide drug candidate OZ439 offers new hope for a single-dose cure of uncomplicated malaria. Proceedings of the National Academy of Sciences, USA 108, 4400–4405.Google Scholar
Claessens, A., Adams, Y., Ghumra, A., Lindergard, G., Buchan, C. C., Andisi, C., Bull, P. C., Mok, S., Gupta, A. P., Wang, C. W., Turner, L., Arman, M., Raza, A., Bozdech, Z. and Rowe, J. A. (2012). A subset of group A-like var genes encodes the malaria parasite ligands for binding to human brain endothelial cells. Proceedings of the National Academy of Sciences, USA 109, E1772–E1781.CrossRefGoogle ScholarPubMed
Cuvillier, A., Redon, F., Antoine, J. C., Chardin, P., DeVos, T. and Merlin, G. (2000). LdARL-3A, a Leishmania promastigote-specific ADP-ribosylation factor-like protein, is essential for flagellum integrity. Journal of Cell Science 113(Pt 11), 2065–2074.CrossRefGoogle ScholarPubMed
Denny, P. W., Gokool, S., Russell, D. G., Field, M. C. and Smith, D. F. (2000). Acylation-dependent protein export in Leishmania. Journal of Biological Chemistry 275, 11017–11025.CrossRefGoogle ScholarPubMed
Derbyshire, E. R., Prudêncio, M., Mota, M. M. and Clardy, J. (2012). Liver-stage malaria parasites vulnerable to diverse chemical scaffolds. Proceedings of the National Academy of Sciences, USA 109, 8511–8516.Google Scholar
Donaldson, J. G. and Jackson, C. L. (2011). ARF family G proteins and their regulators: roles in membrane transport, development and disease. Nature Reviews Molecular Cell Biology 12, 362–375.CrossRefGoogle ScholarPubMed
Dondorp, A. M., Nosten, F., Yi, P., Das, D., Phyo, A. P., Tarning, J., Lwin, K. M., Ariey, F., Hanpithakpong, W., Lee, S. J., Ringwald, P., Silamut, K., Imwong, M., Chotivanich, K., Lim, P., Herdman, T., An, S. S., Yeung, S., Singhasivanon, P., Day, N. P. J., Lindegardh, N., Socheat, D. and White, N. J. (2009). Artemisinin resistance in Plasmodium falciparum malaria. New England Journal of Medicine 361, 455–467.Google Scholar
Farazi, T. A., Manchester, J. K., Waksman, G. and Gordon, J. I. (2001 a). Pre-steady-state kinetic studies of Saccharomyces cerevisiae myristoylCoA:protein N-myristoyltransferase mutants identify residues involved in catalysis. Biochemistry 40, 9177–9186.Google Scholar
Farazi, T. A., Waksman, G. and Gordon, J. I. (2001 b). Structures of Saccharomyces cerevisiae N-myristoyltransferase with bound myristoylCoA and peptide provide insights about substrate recognition and catalysis. Biochemistry 40, 6335–6343.Google Scholar
Fidock, D. A. (2010). Drug discovery: priming the antimalarial pipeline. Nature 465, 297–298.Google Scholar
Frearson, J. A., Brand, S., McElroy, S. P., Cleghorn, L. A., Smid, O., Stojanovski, L., Price, H. P., Guther, M. L., Torrie, L. S., Robinson, D. A., Hallyburton, I., Mpamhanga, C. P., Brannigan, J. A., Wilkinson, A. J., Hodgkinson, M., Hui, R., Qiu, W., Raimi, O. G., van Aalten, D. M., Brenk, R., Gilbert, I. H., Read, K. D., Fairlamb, A. H., Ferguson, M. A., Smith, D. F. and Wyatt, P. G. (2010). N-myristoyltransferase inhibitors as new leads to treat sleeping sickness. Nature 464, 728–732.Google Scholar
Frenal, K., Polonais, V., Marq, J. B., Stratmann, R., Limenitakis, J. and Soldati-Favre, D. (2010). Functional dissection of the apicomplexan glideosome molecular architecture. Cell Host and Microbe 8, 343–357.CrossRefGoogle ScholarPubMed
Gamo, F.-J., Sanz, L. M., Vidal, J., de Cozar, C., Alvarez, E., Lavandera, J.-L., Vanderwall, D. E., Green, D. V. S., Kumar, V., Hasan, S., Brown, J. R., Peishoff, C. E., Cardon, L. R. and Garcia-Bustos, J. F. (2010). Thousands of chemical starting points for antimalarial lead identification. Nature 465, 305–310.Google Scholar
Gelb, M. H., Van Voorhis, W. C., Buckner, F. S., Yokoyama, K., Eastman, R., Carpenter, E. P., Panethymitaki, C., Brown, K. A. and Smith, D. F. (2003). Protein farnesyl and N-myristoyl transferases: piggy-back medicinal chemistry targets for the development of antitrypanosomatid and antimalarial therapeutics. Molecular and Biochemical Parasitology 126, 155–163.Google Scholar
Georgopapadakou, N. H. (2002). Antifungals targeted to protein modification: focus on protein N-myristoyltransferase. Expert Opinion on Investigational Drugs 11, 1117–1125.Google Scholar
Godsel, L. M. and Engman, D. M. (1999). Flagellar protein localization mediated by a calcium-myristoyl/palmitoyl switch mechanism. EMBO Journal 18, 2057–2065.CrossRefGoogle ScholarPubMed
Goldberg, J. (1998). Structural basis for activation of ARF GTPase: mechanisms of guanine nucleotide exchange and GTP-myristoyl switching. Cell 95, 237–248.CrossRefGoogle ScholarPubMed
Goncalves, V., Brannigan, J. A., Thinon, E., Olaleye, T. O., Serwa, R., Lanzarone, S., Wilkinson, A. J., Tate, E. W. and Leatherbarrow, R. J. (2012 a). A fluorescence-based assay for N-myristoyltransferase activity. Analytical Biochemistry 421, 342–344.CrossRefGoogle ScholarPubMed
Goncalves, V., Brannigan, J. A., Whalley, D., Ansell, K. H., Saxty, B., Holder, A. A., Wilkinson, A. J., Tate, E. W. and Leatherbarrow, R. J. (2012 b). Discovery of Plasmodium vivax N-myristoyltransferase inhibitors: screening, synthesis, and structural characterization of their binding mode. Journal of Medicinal Chemistry 55, 3578–3582.Google Scholar
Guiguemde, W. A., Shelat, A. A., Bouck, D., Duffy, S., Crowther, G. J., Davis, P. H., Smithson, D. C., Connelly, M., Clark, J., Zhu, F., Jiménez-Díaz, M. B., Martinez, M. S., Wilson, E. B., Tripathi, A. K., Gut, J., Sharlow, E. R., Bathurst, I., Mazouni, F. E., Fowble, J. W., Forquer, I., McGinley, P. L., Castro, S., Angulo-Barturen, I., Ferrer, S., Rosenthal, P. J., DeRisi, J. L., Sullivan, D. J., Lazo, J. S., Roos, D. S., Riscoe, M. K., Phillips, M. A., Rathod, P. K., Van Voorhis, W. C., Avery, V. M. and Guy, R. K. (2010). Chemical genetics of Plasmodium falciparum. Nature 465, 311–315.Google Scholar
Gunaratne, R. S., Sajid, M., Ling, I. T., Tripathi, R., Pachebat, J. A. and Holder, A. A. (2000). Characterization of N-myristoyltransferase from Plasmodium falciparum. Biochemical Journal 348 (Pt 2), 459–463.Google Scholar
Hang, H. C., Wilson, J. P. and Charron, G. (2011). Bioorthogonal chemical reporters for analyzing protein lipidation and lipid trafficking. Accounts of Chemical Research 44, 699–708.CrossRefGoogle ScholarPubMed
Heal, W. P. and Tate, E. W. (2010). Getting a chemical handle on protein post-translational modification. Organic and Biomolecular Chemistry 8, 731–738.CrossRefGoogle ScholarPubMed
Hertz-Fowler, C., Ersfeld, K. and Gull, K. (2001). CAP5.5, a life-cycle-regulated, cytoskeleton-associated protein is a member of a novel family of calpain-related proteins in Trypanosoma brucei. Molecular and Biochemical Parasitology 116, 25–34.Google Scholar
Hopkins, A. L., Groom, C. R. and Alex, A. (2004). Ligand efficiency: a useful metric for lead selection. Drug Discovery Today 9, 430–431.Google Scholar
Jones, M. L., Kitson, E. L. and Rayner, J. C. (2006). Plasmodium falciparum erythrocyte invasion: a conserved myosin associated complex. Molecular and Biochemical Parasitology 147, 74–84.CrossRefGoogle ScholarPubMed
Jones, M. L., Collins, M. O., Goulding, D., Choudhary, J. S. and Rayner, J. C. (2012). Analysis of protein palmitoylation reveals a pervasive role in Plasmodium development and pathogenesis. Cell Host and Microbe 12, 246–258.Google Scholar
Kappe, S. H. I., Vaughan, A. M., Boddey, J. A. and Cowman, A. F. (2010). That was then but this is now: malaria research in the time of an eradication agenda. Science 328, 862–866.Google Scholar
Kato, N., Sakata, T., Breton, G., Le Roch, K. G., Nagle, A., Andersen, C., Bursulaya, B., Henson, K., Johnson, J., Kumar, K. A., Marr, F., Mason, D., McNamara, C., Plouffe, D., Ramachandran, V., Spooner, M., Tuntland, T., Zhou, Y., Peters, E. C., Chatterjee, A., Schultz, P. G., Ward, G. E., Gray, N., Harper, J. and Winzeler, E. A. (2008). Gene expression signatures and small-molecule compounds link a protein kinase to Plasmodium falciparum motility. Nature Chemical Biology 4, 347–356.CrossRefGoogle Scholar
Krafts, K., Hempelmann, E. and Skórska-Stania, A. (2012). From methylene blue to chloroquine: a brief review of the development of an antimalarial therapy. Parasitology Research 111, 1–6.Google Scholar
Leber, W., Skippen, A., Fivelman, Q. L., Bowyer, P. W., Cockcroft, S. and Baker, D. A. (2009). A unique phosphatidylinositol 4-phosphate 5-kinase is activated by ADP-ribosylation factor in Plasmodium falciparum. International Journal for Parasitology 39, 645–653.Google Scholar
Li, J. and Zhou, B. (2010). Biological actions of artemisinin: insights from medicinal chemistry studies. Molecules 15, 1378–1397.Google Scholar
Lodge, J. K., Johnson, R. L., Weinberg, R. A. and Gordon, J. I. (1994). Comparison of myristoyl-CoA:protein N-myristoyltransferases from three pathogenic fungi: Cryptococcus neoformans, Histoplasma capsulatum, and Candida albicans. Journal of Biological Chemistry 269, 2996–3009.Google Scholar
Loeb, F., Clark, W. M., Coatney, G. R., Coggeshall, L. T., Dieuaide, F. R., Dochez, A. R., Hakansson, E. G., Marshall, E. K., Marvel, C. S., McCoy, O. R., Sapero, J. J., Sebrell, W. H., Shannon, J. A. and Carden, G. A. (1946). Activity of a new antimalarial agent, chloroquine (SN 7618) statement approved by the board for coordination of malarial studies. Journal of the American Medical Association 130, 1069–1070.CrossRefGoogle Scholar
Mackinnon, M. J. and Marsh, K. (2010). The selection landscape of malaria parasites. Science 328, 866–871.CrossRefGoogle ScholarPubMed
Maroof, A., Brown, N., Smith, B., Hodgkinson, M. R., Maxwell, A., Losch, F. O., Fritz, U., Walden, P., Lacey, C. N. J., Smith, D. F., Aebischer, T. and Kaye, P. M. (2012). Therapeutic vaccination with recombinant adenovirus reduces splenic parasite burden in experimental visceral leishmaniasis. Journal of Infectious Diseases 205, 853–863.Google Scholar
Martinez, A., Traverso, J. A., Valot, B., Ferro, M., Espagne, C., Ephritikhine, G., Zivy, M., Giglione, C. and Meinnel, T. (2008). Extent of N-terminal modifications in cytosolic proteins from eukaryotes. Proteomics 8, 2809–2831.Google Scholar
Masubuchi, M., Kawasaki, K., Ebiike, H., Ikeda, Y., Tsujii, S., Sogabe, S., Fujii, T., Sakata, K., Shiratori, Y., Aoki, Y., Ohtsuka, T. and Shimma, N. (2001). Design and synthesis of novel benzofurans as a new class of antifungal agents targeting fungal N-myristoyltransferase. Part 1. Bioorganic and Medicinal Chemistry Letters 11, 1833–1837.Google Scholar
Maurer-Stroh, S., Eisenhaber, B. and Eisenhaber, F. (2002 a). N-terminal N-myristoylation of proteins: prediction of substrate proteins from amino acid sequence. Journal of Molecular Biology 317, 541–557.Google Scholar
Maurer-Stroh, S., Eisenhaber, B. and Eisenhaber, F. (2002 b). N-terminal N-myristoylation of proteins: refinement of the sequence motif and its taxon-specific differences. Journal of Molecular Biology 317, 523–540.Google Scholar
Meister, S., Plouffe, D. M., Kuhen, K. L., Bonamy, G. M. C., Wu, T., Barnes, S. W., Bopp, S. E., Borboa, R., Bright, A. T., Che, J., Cohen, S., Dharia, N. V., Gagaring, K., Gettayacamin, M., Gordon, P., Groessl, T., Kato, N., Lee, M. C. S., McNamara, C. W., Fidock, D. A., Nagle, A., Nam, T.-G., Richmond, W., Roland, J., Rottmann, M., Zhou, B., Froissard, P., Glynne, R. J., Mazier, D., Sattabongkot, J., Schultz, P. G., Tuntland, T., Walker, J. R., Zhou, Y., Chatterjee, A., Diagana, T. T. and Winzeler, E. A. (2011). Imaging of Plasmodium liver stages to drive next-generation antimalarial drug discovery. Science 334, 1372–1377.Google Scholar
Miller, L. H. and Su, X. (2011). Artemisinin: discovery from the Chinese herbal garden. Cell 146, 855–858.Google Scholar
Mills, E., Price, H. P., Johner, A., Emerson, J. E. and Smith, D. F. (2007). Kinetoplastid PPEF phosphatases: dual acylated proteins expressed in the endomembrane system of Leishmania. Molecular and Biochemical Parasitology 152, 22–34.Google Scholar
Moskes, C., Burghaus, P. A., Wernli, B., Sauder, U., Durrenberger, M. and Kappes, B. (2004). Export of Plasmodium falciparum calcium-dependent protein kinase 1 to the parasitophorous vacuole is dependent on three N-terminal membrane anchor motifs. Molecular Microbiology 54, 676–691.Google Scholar
Murray, C. J. L., Rosenfeld, L. C., Lim, S. S., Andrews, K. G., Foreman, K. J., Haring, D., Fullman, N., Naghavi, M., Lozano, R. and Lopez, A. D. (2012). Global malaria mortality between 1980 and 2010: a systematic analysis. Lancet 379, 413–431.Google Scholar
Ntwasa, M., Egerton, M. and Gay, N. J. (1997). Sequence and expression of Drosophila myristoyl-CoA: protein N-myristoyl transferase: evidence for proteolytic processing and membrane localisation. Journal of Cell Science 110(Pt 2), 149–156.Google Scholar
Ohtsuka, T. and Aoki, I. (2003). N-Myristoyltransferase inhibitors as potential antifungal drugs. Drugs of the Future 28, 143–152.CrossRefGoogle Scholar
Olego-Fernandez, S., Vaughan, S., Shaw, M. K., Gull, K. and Ginger, M. L. (2009). Cell morphogenesis of Trypanosoma brucei requires the paralogous, differentially expressed calpain-related proteins CAP5.5 and CAP5.5V. Protist 160, 576–590.Google Scholar
O'Neill, P. M. and Posner, G. H. (2004). A medicinal chemistry perspective on artemisinin and related endoperoxides. Journal of Medicinal Chemistry 47, 2945–2964.Google Scholar
O'Neill, P. M., Amewu, R. K., Nixon, G. L., Bousejra ElGarah, F., Mungthin, M., Chadwick, J., Shone, A. E., Vivas, L., Lander, H., Barton, V., Muangnoicharoen, S., Bray, P. G., Davies, J., Park, B. K., Wittlin, S., Brun, R., Preschel, M., Zhang, K. and Ward, S. A. (2010). Identification of a 1,2,4,5-tetraoxane antimalarial drug-development candidate (RKA 182) with superior properties to the semisynthetic artemisinins. Angewandte Chemie International Edition 49, 5693–5697.Google Scholar
Painter, H. J., Morrisey, J. M., Mather, M. W. and Vaidya, A. B. (2007). Specific role of mitochondrial electron transport in blood-stage Plasmodium falciparum. Nature 446, 88–91.Google Scholar
Panethymitaki, C., Bowyer, P. W., Price, H. P., Leatherbarrow, R. J., Brown, K. A. and Smith, D. F. (2006). Characterization and selective inhibition of myristoyl-CoA:protein N-myristoyltransferase from Trypanosoma brucei and Leishmania major. Biochemical Journal 396, 277–285.Google Scholar
Phyo, A. P., Nkhoma, S., Stepniewska, K., Ashley, E. A., Nair, S., McGready, R., ler Moo, C., Al-Saai, S., Dondorp, A. M., Lwin, K. M., Singhasivanon, P., Day, N. P., White, N. J., Anderson, T. J. and Nosten, F. (2012). Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study. Lancet 379, 1960–1966.Google Scholar
Pino, P., Sebastian, S., Kim, E. A., Bush, E., Brochet, M., Volkmann, K., Kozlowski, E., Llinás, M., Billker, O. and Soldati-Favre, D. (2012). A tetracycline-repressible transactivator system to study essential genes in malaria parasites. Cell Host and Microbe 12, 824–834.Google Scholar
Plouffe, D., Brinker, A., McNamara, C., Henson, K., Kato, N., Kuhen, K., Nagle, A., Adrián, F., Matzen, J. T., Anderson, P., Nam, T.-G., Gray, N. S., Chatterjee, A., Janes, J., Yan, S. F., Trager, R., Caldwell, J. S., Schultz, P. G., Zhou, Y. and Winzeler, E. A. (2008). In silico activity profiling reveals the mechanism of action of antimalarials discovered in a high-throughput screen. Proceedings of the National Academy of Sciences, USA 105, 9059–9064.Google Scholar
Price, H. P., Menon, M. R., Panethymitaki, C., Goulding, D., McKean, P. G. and Smith, D. F. (2003). Myristoyl-CoA:protein N-myristoyltransferase, an essential enzyme and potential drug target in kinetoplastid parasites. Journal of Biological Chemistry 278, 7206–7214.Google Scholar
Price, H. P., Panethymitaki, C., Goulding, D. and Smith, D. F. (2005). Functional analysis of TbARL1, an N-myristoylated Golgi protein essential for viability in bloodstream trypanosomes. Journal of Cell Science 118, 831–841.Google Scholar
Price, H. P., Stark, M. and Smith, D. F. (2007). Trypanosoma brucei ARF1 plays a central role in endocytosis and Golgi-lysosome trafficking. Molecular Biology of the Cell 18, 864–873.Google Scholar
Price, H. P., Guther, M. L., Ferguson, M. A. and Smith, D. F. (2010). Myristoyl-CoA:protein N-myristoyltransferase depletion in trypanosomes causes avirulence and endocytic defects. Molecular and Biochemical Parasitology 169, 55–58.Google Scholar
Price, H. P., Hodgkinson, M. R., Wright, M. H., Tate, E. W., Smith, B. A., Carrington, M., Stark, M. and Smith, D. F. (2012). A role for the vesicle-associated tubulin binding protein ARL6 (BBS3) in flagellum extension in Trypanosoma brucei. Biochimica et Biophysica Acta 1823, 1178–1191.Google Scholar
Price, R. N., Douglas, N. M. and Anstey, N. M. (2009). New developments in Plasmodium vivax malaria: severe disease and the rise of chloroquine resistance. Current Opinion in Infectious Diseases 22, 430–435.Google Scholar
Proto, W. R., Castanys-Munoz, E., Black, A., Tetley, L., Moss, C. X., Juliano, L., Coombs, G. H. and Mottram, J. C. (2011). Trypanosoma brucei metacaspase 4 is a pseudopeptidase and a virulence factor. Journal of Biological Chemistry 286, 39914–39925.Google Scholar
Rackham, M. D., Brannigan, J. A., Moss, D. K., Yu, Z., Wilkinson, A. J., Holder, A. A., Tate, E. W. and Leatherbarrow, R. J. (2013). Discovery of Novel and Ligand-Efficient Inhibitors of Plasmodium falciparum and Plasmodium vivax N-Myristoyltransferase. Journal of Medicinal Chemistry 56, 371–375, DOI: 10.1021/jm301474t.Google Scholar
Rahlfs, S., Koncarevic, S., Iozef, R., Mailu, B. M., Savvides, S. N., Schirmer, R. H. and Becker, K. (2009). Myristoylated adenylate kinase-2 of Plasmodium falciparum forms a heterodimer with myristoyltransferase. Molecular and Biochemical Parasitology 163, 77–84.Google Scholar
Rees-Channer, R. R., Martin, S. R., Green, J. L., Bowyer, P. W., Grainger, M., Molloy, J. E. and Holder, A. A. (2006). Dual acylation of the 45 kDa gliding-associated protein (GAP45) in Plasmodium falciparum merozoites. Molecular and Biochemical Parasitology 149, 113–116.Google Scholar
Resh, M. D. (1994). Myristylation and palmitylation of Src family members: the fats of the matter. Cell 76, 411–413.Google Scholar
Resh, M. D. (2006 a). Trafficking and signaling by fatty-acylated and prenylated proteins. Nature Chemical Biology 2, 584–590.Google Scholar
Resh, M. D. (2006 b). Use of analogs and inhibitors to study the functional significance of protein palmitoylation. Methods 40, 191–197.Google Scholar
Ridzuan, M. A., Moon, R. W., Knuepfer, E., Black, S., Holder, A. A. and Green, J. L. (2012). Subcellular location, phosphorylation and assembly into the motor complex of GAP45 during Plasmodium falciparum schizont development. PLoS ONE 7, e33845.Google Scholar
Rodrigues, T., Prudencio, M., Moreira, R., Mota, M. M. and Lopes, F. (2012). Targeting the liver stage of malaria parasites: a yet unmet goal. Journal of Medicinal Chemistry 55, 995–1012.Google Scholar
Roth, A. F., Wan, J., Green, W. N., Yates, J. R. and Davis, N. G. (2006). Proteomic identification of palmitoylated proteins. Methods 40, 135–142.Google Scholar
Rottmann, M., McNamara, C., Yeung, B. K. S., Lee, M. C. S., Zou, B., Russell, B., Seitz, P., Plouffe, D. M., Dharia, N. V., Tan, J., Cohen, S. B., Spencer, K. R., Gonzalez-Paez, G. E., Lakshminarayana, S. B., Goh, A., Suwanarusk, R., Jegla, T., Schmitt, E. K., Beck, H.-P., Brun, R., Nosten, F., Renia, L., Dartois, V., Keller, T. H., Fidock, D. A., Winzeler, E. A. and Diagana, T. T. (2010). Spiroindolones, a potent compound class for the treatment of malaria. Science 329, 1175–1180.CrossRefGoogle ScholarPubMed
Rudnick, D. A., McWherter, C. A., Rocque, W. J., Lennon, P. J., Getman, D. P. and Gordon, J. I. (1991). Kinetic and structural evidence for a sequential ordered Bi Bi mechanism of catalysis by Saccharomyces cerevisiae myristoyl – CoA:protein N-myristoyltransferase. Journal of Biological Chemistry 266, 9732–9739.Google Scholar
Russo, I., Oksman, A. and Goldberg, D. E. (2009 a). Fatty acid acylation regulates trafficking of the unusual Plasmodium falciparum calpain to the nucleolus. Molecular Microbiology 72, 229–245.CrossRefGoogle ScholarPubMed
Russo, I., Oksman, A., Vaupel, B. and Goldberg, D. E. (2009 b). A calpain unique to alveolates is essential in Plasmodium falciparum and its knockdown reveals an involvement in pre-S-phase development. Proceedings of the National Academy of Sciences, USA 106, 1554–1559.Google Scholar
Sadlova, J., Price, H. P., Smith, B. A., Votypka, J., Volf, P. and Smith, D. F. (2010). The stage-regulated HASPB and SHERP proteins are essential for differentiation of the protozoan parasite Leishmania major in its sand fly vector, Phlebotomus papatasi. Cellular Microbiology 12, 1765–1779.Google Scholar
Sahin, A., Espiau, B., Tetaud, E., Cuvillier, A., Lartigue, L., Ambit, A., Robinson, D. R. and Merlin, G. (2008). The leishmania ARL-1 and Golgi traffic. PLoS ONE 3, e1620.CrossRefGoogle ScholarPubMed
Sebastian, S., Brochet, M., Collins, M. O., Schwach, F., Jones, M. L., Goulding, D., Rayner, J. C., Choudhary, J. S. and Billker, O. (2012). A Plasmodium calcium-dependent protein kinase controls zygote development and transmission by translationally activating repressed mRNAs. Cell Host and Microbe 12, 9–19.Google Scholar
Shaw, B. D., Momany, C. and Momany, M. (2002). Aspergillus nidulans swoF encodes an N-myristoyl transferase. Eukaryotic Cell 1, 241–248.Google Scholar
Slack, R. D., Jacobine, A. M. and Posner, G. H. (2012). Antimalarial peroxides: advances in drug discovery and design. MedChemComm 3, 281–297.Google Scholar
Sleigh, S. H. and Barton, C. L. (2010). Repurposing strategies for therapeutics. Pharmaceutical Medicine 24, 151–159.Google Scholar
Struck, N. S., de Souza Dias, S., Langer, C., Marti, M., Pearce, J. A., Cowman, A. F. and Gilberger, T. W. (2005). Re-defining the Golgi complex in Plasmodium falciparum using the novel Golgi marker PfGRASP. Journal of Cell Science 118, 5603–5613.Google Scholar
Sturm, A., Amino, R., van de Sand, C., Regen, T., Retzlaff, S., Rennenberg, A., Krueger, A., Pollok, J.-M., Menard, R. and Heussler, V. T. (2006). Manipulation of host hepatocytes by the malaria parasite for delivery into liver sinusoids. Science 313, 1287–1290.Google Scholar
Tewari, R., Straschil, U., Bateman, A., Bohme, U., Cherevach, I., Gong, P., Pain, A. and Billker, O. (2010). The systematic functional analysis of Plasmodium protein kinases identifies essential regulators of mosquito transmission. Cell Host and Microbe 8, 377–387.Google Scholar
Towler, D. A., Adams, S. P., Eubanks, S. R., Towery, D. S., Jackson-Machelski, E., Glaser, L. and Gordon, J. I. (1987). Purification and characterization of yeast myristoyl CoA:protein N-myristoyltransferase. Proceedings of the National Academy of Sciences, USA 84, 2708–2712.Google Scholar
Tull, D., Vince, J. E., Callaghan, J. M., Naderer, T., Spurck, T., McFadden, G. I., Currie, G., Ferguson, K., Bacic, A. and McConville, M. J. (2004). SMP-1, a member of a new family of small myristoylated proteins in kinetoplastid parasites, is targeted to the flagellum membrane in Leishmania. Molecular Biology of the Cell 15, 4775–4786.Google Scholar
Tull, D., Heng, J., Gooley, P. R., Naderer, T. and McConville, M. J. (2012). Acylation-dependent and-independent membrane targeting and distinct functions of small myristoylated proteins (SMPs) in Leishmania major. International Journal for Parasitology 42, 239–247.Google Scholar
Tyers, M. and Mann, M. (2003). From genomics to proteomics. Nature 422, 193–197.Google Scholar
Udomsangpetch, R., Somsri, S., Panichakul, T., Chotivanich, K., Sirichaisinthop, J., Yang, Z., Cui, L. and Sattabongkot, J. (2007). Short-term in vitro culture of field isolates of Plasmodium vivax using umbilical cord blood. Parasitology International 56, 65–69.Google Scholar
Vennerstrom, J. L., Arbe-Barnes, S., Brun, R., Charman, S. A., Chiu, F. C. K., Chollet, J., Dong, Y., Dorn, A., Hunziker, D., Matile, H., McIntosh, K., Padmanilayam, M., Santo Tomas, J., Scheurer, C., Scorneaux, B., Tang, Y., Urwyler, H., Wittlin, S. and Charman, W. N. (2004). Identification of an antimalarial synthetic trioxolane drug development candidate. Nature 430, 900–904.Google Scholar
Weissbuch, I. and Leiserowitz, L. (2008). Interplay between malaria, crystalline hemozoin formation, and antimalarial drug action and design. Chemical Reviews 108, 4899–4914.Google Scholar
Weston, S. A., Camble, R., Colls, J., Rosenbrock, G., Taylor, I., Egerton, M., Tucker, A. D., Tunnicliffe, A., Mistry, A., Mancia, F., de la Fortelle, E., Irwin, J., Bricogne, G. and Pauptit, R. A. (1998). Crystal structure of the anti-fungal target N-myristoyl transferase. Nature Structural Biology 5, 213–221.Google Scholar
WHO (2011). World Malaria Report 2011. World Health Organization, Geneva, Switzerland.Google Scholar
Winkelmann, E. and Raether, W. (1978). Chemotherapeutically active nitro-compounds 0.4. 5-nitroimidazoles 0.3. Arzneimittel-Forschung/Drug Research 28–1, 739–749.Google Scholar
Wright, M. H., Heal, W. P., Mann, D. J. and Tate, E. W. (2010). Protein myristoylation in health and disease. Journal of Chemical Biology 3, 19–35.Google Scholar
Wyllie, S., Patterson, S., Stojanovski, L., Simeons, F. R., Norval, S., Kime, R., Read, K. D. and Fairlamb, A. H. (2012). The anti-trypanosome drug fexinidazole shows potential for treating visceral leishmaniasis. Science Translational Medicine 4, 119re111.Google Scholar
Yu, Z., Brannigan, J. A., Moss, D. K., Brzozowski, A. M., Wilkinson, A. J., Holder, A. A., Tate, E. W. and Leatherbarrow, R. J. (2012). Design and synthesis of inhibitors of Plasmodium falciparum N-myristoyltransferase, a promising target for anti-malarial drug discovery. Journal of Medicinal Chemistry 55, 8879–8890.Google Scholar
Zha, J., Weiler, S., Oh, K. J., Wei, M. C. and Korsmeyer, S. J. (2000). Posttranslational N-myristoylation of BID as a molecular switch for targeting mitochondria and apoptosis. Science 290, 1761–1765.Google Scholar