Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

A pre-emptive strike against malaria's stealthy hepatic forms

Nature Reviews Drug Discovery volume 8, pages 854–864 (2009)Cite this article

Abstract

Almost all the drugs that are widely used today against Plasmodium spp., the causative agent of malaria, target the asexual blood stages of the parasite. Widespread drug resistance severely restricts our ability to control malaria and makes it necessary to seek novel antimalarial compounds. Here, we advocate the development of true causal chemoprophylactic drugs that will fully inhibit the obligate short-lived hepatic forms that precede blood infections. Such drugs will prevent pathology and interrupt transmission, and could therefore have an important role in the control of malaria and its eventual eradication.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The Plasmodium life cycle.
Figure 2: Discovery path for drugs against the Plasmodium liver stages.

Similar content being viewed by others

References

  1. White, N. J. et al. Averting a malaria disaster. Lancet 353, 1965–1967 (1999).

    Article  CAS  PubMed  Google Scholar 

  2. Newton, P. N. & White, N. J. Malaria: new developments in treatment and prevention. Ann. Rev. Med. 50, 179–192 (1999).

    Article  CAS  PubMed  Google Scholar 

  3. White, N. J. Antimalarial drug resistance and combination chemotherapy. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 354, 739–749 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Noedl, H. et al. Evidence of artemisinin-resistant malaria in western Cambodia. New Engl. J. Med. 359, 2619–2620 (2008).

    Article  CAS  PubMed  Google Scholar 

  5. Baird, J. K. et al. Resistance to chloroquine by Plasmodium vivax in Irian Jaya, Indonesia. Am. J. Trop. Med. Hyg. 44, 547–552 (1991).

    Article  CAS  PubMed  Google Scholar 

  6. Rieckmann, K. H., Davis, D. R. & Hutton, D. C. Plasmodium vivax resistance to chloroquine? Lancet 334, 1183–1184 (1989).

    Article  Google Scholar 

  7. Bunnag, D. et al. High dose of primaquine in primaquine resistant vivax malaria. Trans. Royal Soc. Trop. Med. Hyg. 88, 218–219 (1994).

    Article  CAS  Google Scholar 

  8. Luzzi, G. A., Warrell, D. A., Barnes, A. J. & Dunbar, E. M. Treatment of primaquine-resistant Plasmodium vivax malaria. Lancet 340, 310 (1992).

    Article  CAS  PubMed  Google Scholar 

  9. Mendis, K. N., Sina, B. J., Marchesini, P. & Carter, R. The neglected burden of Plasmodium vivax malaria. Am. J. Trop.Med. Hyg. 64, 97–106 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Rogerson, S. J. & Carter, R. Severe vivax malaria: newly recognised or rediscovered? PLoS Med. 5, e136 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Tjitra, E. et al. Multidrug-resistant Plasmodium vivax associated with severe and fatal malaria: a prospective study in Papua, Indonesia. PLoS Med. 5, e128 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Shortt, H. E. & Garnham, P. C. C. Pre-erythrocytic stage in mammalian malaria parasites. Nature 161, 126 (1948).

    Article  CAS  PubMed  Google Scholar 

  13. Bray, R. S. Studies on the exo-erythrocytic cycle in the genus Plasmodium (H. K. Lewis & Co., London, 1957).

    Google Scholar 

  14. Krotoski, W. A. et al. Relapses in primate malaria: discovery of two populations of exoerythrocytic stages. Preliminary note. BMJ 280, 153–154 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Garnham, P. C. C. Malaria Parasites and Other Haemosporidia (Blackwell Scientific Publications, Oxford, 1966).

    Google Scholar 

  16. Cox, F. E. G. in Malaria: Principles and Practice of Malariology (eds. Wernsdorfer, W. H. & McGregor, I.) 1503–1543 (Churchill Livingstone, London, 1988).

    Google Scholar 

  17. Landau, I. & Boulard, Y. in Rodent Malaria (eds. Killick-Kendrick, R. & Peters, W.) 53–84 (Academic Press, London, New York, San Francisco, 1978).

    Google Scholar 

  18. Lupascu, G. et al. The late primary exo-erythrocytic stages of Plasmodium malariae. Trans. Royal Soc.Trop. Med. Hyg. 61, 482–489 (1967).

    Article  CAS  Google Scholar 

  19. Boyd, M. F. & Kitchen, S. F. Observations on induced falciparum malaria. Am. J. Trop. Med. 17, 213–235 (1937).

    Article  Google Scholar 

  20. Boyd, M. F. & Stratman-Thomas, W. K. Studies on benign tertian malaria. 7. Some observations on inoculation and onset. Am. J. Hyg. 20, 488–495 (1934).

    Google Scholar 

  21. Bray, R. S. The exoerythrocytic phase of malaria parasites. Int. Rev. Trop. Med. 2, 41–74 (1963).

    CAS  PubMed  Google Scholar 

  22. Fairley, N. H. Sidelights on malaria in man obtained by subinoculation experiments. Trans. Royal Soc. Trop. Med. Hyg. 40, 621–676 (1947).

    Article  CAS  Google Scholar 

  23. Bray, R. S. The tissue phase of malaria parasites. J. Trop. Med. Hyg. 57, 41–45 (1954).

    CAS  PubMed  Google Scholar 

  24. Vanderberg, J. P. Asynchronous maturation of Plasmodium berghei exo-erythrocytic forms in rats. Trans. Royal Soc. Trop. Med. Hyg. 76, 251–252 (1982).

    Article  CAS  Google Scholar 

  25. Kitchen, S. F. in Malariology — A Comprehensive Survey of All Aspects of This Group of Diseases From a Global Standpoint (ed. Boyd, M. F.) 966–994 (W. B. Saunders Company, Philadelphia and London, 1949).

    Google Scholar 

  26. Haynes, J. D., Diggs, C. L., Hines, F. A. & Desjardins, R. E. Culture of human malaria parasites Plasmodium falciparum. Nature 263, 767–769 (1976).

    Article  CAS  PubMed  Google Scholar 

  27. Trager, W. & Jensen, J. B. Human malaria parasites in continuous culture. Science 193, 673–675 (1976).

    Article  CAS  PubMed  Google Scholar 

  28. Al-Olayan, E. M., Beetsma, A. L., Butcher, G. A., Sinden, R. E. & Hurd, H. Complete development of mosquito phases of the malaria parasite in vitro. Science 295, 677–679 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Porter-Kelley, J. M. et al. Plasmodium yoelii: axenic development of the parasite mosquito stages. Exp. Parasitol. 112, 99–108 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Luke, T. C. & Hoffman, S. L. Rationale and plans for developing a non-replicating, metabolically active, radiation-attenuated Plasmodium falciparum sporozoite vaccine. J. Exp. Biol. 206, 3803–3808 (2003).

    Article  PubMed  Google Scholar 

  31. Coatney, G. R. & Cooper, W. C. Symposium on exoerythrocytic forms of malarial parasites. III. The chemotherapy of malaria in relation to our knowledge of exoerythrocytic forms. J. Parasitol. 34, 275–289 (1948).

    Article  CAS  PubMed  Google Scholar 

  32. Landau, I. Description of Plasmodium chabaudi n. sp., parasite of African rodents. C. R. Hebd. Séances Acad. Sci. 260, 3758–3761 (1965) (in French).

    CAS  PubMed  Google Scholar 

  33. Landau, I. & Chabaud, A. G. Natural infection by 2 plasmodia of the rodent Thamnomys rutilans in the Central African Republic. C. R. Hebd. Séances Acad. Sci. 261, 230–232 (1965) (in French).

    CAS  Google Scholar 

  34. Rodhain, J. Plasmodium vinckei n. sp.; second plasmodium parasite of wild rodents at Katange. Ann. Soc. Belge Méd. Trop. 32, 275–279 (1952) (in French).

    CAS  PubMed  Google Scholar 

  35. Vincke, I. H. & Lips, M. A. H. Un nouveau plasmodium d'un rongeur sauvage du Congon, Plasmodium berghei n. sp. Ann. Soc. Belge Méd. Trop. 28, 97–104 (1948) (in French).

    CAS  PubMed  Google Scholar 

  36. Yoeli, M. & Wall, W. J. Complete sporogonic development of Plasmodium berghei in experimentally infected Anopheles spp. Nature 168, 1078–1080 (1951).

    Article  CAS  PubMed  Google Scholar 

  37. Peters, W. Chemotherapy and drug resistance in malaria (Academic Press, London and New York, 1970).

    Google Scholar 

  38. Schmidt, L. H. Plasmodium cynomolgi infections in the rhesus monkey. Background studies. Am. J. Trop. Med. Hyg. 31, 609–611 (1982).

    Article  CAS  PubMed  Google Scholar 

  39. Schmidt, L. H. et al. Antimalarial activities and subacute toxicity of RC-12, a 4-amino-substituted pyrocatechol. Antimicrob. Agents Chemother. 28, 612–625 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Herrera, S., Perlaza, B. L., Bonelo, A. & Arévalo-Herrera, M. Aotus monkeys: their great value for anti-malaria vaccines and drug testing. Int. J. Parasitol. 32, 1625–1635 (2002).

    Article  PubMed  Google Scholar 

  41. Collins, W. E. Nonhuman primate models. II. Infection of Saimiri and Aotus monkeys with Plasmodium vivax. Methods Mol. Med. 72, 85–92 (2002).

    PubMed  Google Scholar 

  42. Collins, W. E. Nonhuman primate models. I. Nonhuman primate host-parasite combinations. Methods Mol. Med. 72, 77–84 (2002).

    PubMed  Google Scholar 

  43. Badell, E. et al. Human malaria in immunocompromised mice: an in vivo model to study defense mechanisms against Plasmodium falciparum. J. Exp. Med. 192, 1653–1660 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Moreno, A., Badell, E., Van Rooijen, N. & Druilhe, P. Human malaria in immunocompromised mice: new in vivo model for chemotherapy studies. Antimicrob. Agents Chemother. 45, 1847–1853 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Moreno, A. et al. The course of infections and pathology in immunomodulated NOD/LtSz-SCID mice inoculated with Plasmodium falciparum laboratory lines and clinical isolates. Int. J. Parasitol. 36, 361–369 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Moreno, A., Perignon, J. L., Morosan, S., Mazier, D. & Benito, A. Plasmodium falciparum-infected mice: more than a tour de force. Trends Parasitol. 23, 254–259 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Grompe, M. Mouse liver goes human: a new tool in experimental hepatology. Hepatology 33, 1005–1006 (2001).

    Article  CAS  PubMed  Google Scholar 

  48. Kneteman, N. M. & Mercer, D. F. Mice with chimeric human livers: who says supermodels have to be tall? Hepatology 41, 703–706 (2005).

    Article  CAS  PubMed  Google Scholar 

  49. Morosan, S. et al. Liver-stage development of Plasmodium falciparum, in a humanized mouse model. J. Infect. Dis. 193, 996–1004 (2006).

    Article  CAS  PubMed  Google Scholar 

  50. Sacci, J. B. Jr et al. Plasmodium falciparum infection and exoerythrocytic development in mice with chimeric human livers. Int. J. Parasitol. 36, 353–360 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Azuma, H. et al. Robust expansion of human hepatocytes in Fah−/−/Rag2−/−/Il2rg−/− mice. Nature Biotech. 25, 903–910 (2007).

    Article  CAS  Google Scholar 

  52. Hollingdale, M. R., Leef, J. L., McCullough, M. & Beaudoin, R. L. In vitro cultivation of the exoerythrocytic stage of Plasmodium berghei from sporozoites. Science 213, 1021–1022 (1981).

    Article  CAS  PubMed  Google Scholar 

  53. Hollingdale, M. R., Leland, P. & Schwartz, A. L. In vitro cultivation of the exoerythrocytic stage of Plasmodium berghei in a hepatoma cell line. Am. J. Trop. Med. Hyg. 32, 682–684 (1983).

    Article  CAS  PubMed  Google Scholar 

  54. Lambiotte, M., Landau, I., Thierry, N. & Miltgen, F. Development of schizonts in cultured hepatocytes of adult rats after in vitro infection with Plasmodium yoelii sporoazoites. C. R. Hebd. Séances Acad. Sci. 293, 431–433 (1981) (in French).

    CAS  Google Scholar 

  55. Pirson, P. Culture of the exoerythrocytic liver stages of Plasmodium berghei sporozoites in rat hepatocytes. Trans. Royal Soc. Trop. Med. Hyg. 76, 422 (1982).

    Article  CAS  Google Scholar 

  56. Mazier, D. et al. In vitro infection of adult Thamnomys hepatocytes by sporozoites of Plasmodium yoelii: development of schizonts and release of infective merozoites. Ann. Parasitol. Hum. Comp. 57, 99–100 (1982) (in French).

    Article  CAS  PubMed  Google Scholar 

  57. Rénia, L. et al. A malaria heat-shock-like determinant expressed on the infected hepatocyte surface is the target of antibody-dependent cell-mediated cytotoxic mechanisms by nonparenchymal liver cells. Eur. J. Immunol. 20, 1445–1449 (1990).

    Article  PubMed  Google Scholar 

  58. Mazier, D. et al. Complete development of hepatic stages of Plasmodium falciparum in vitro. Science 227, 440–442 (1985).

    Article  CAS  PubMed  Google Scholar 

  59. Mazier, D. et al. Cultivation of the liver forms of Plasmodium vivax in human hepatocytes. Nature 307, 367–369 (1984).

    Article  CAS  PubMed  Google Scholar 

  60. Mazier, D. et al. Plasmodium ovale: in vitro development of hepatic stages. Exp. Parasitol. 64, 393–400 (1987).

    Article  CAS  PubMed  Google Scholar 

  61. Smith, J. E., Meis, J. F., Ponnudurai, T., Verhave, J. P. & Moshage, H. J. In vitro culture of exoerythrocytic form of Plasmodium falciparum in adult human hepatocytes. Lancet 2, 757–758 (1984).

    Article  CAS  PubMed  Google Scholar 

  62. Millet, P. G., Collins, W. E., Fisk, T. L. & Nguyen-Dinh, P. In vitro cultivation of exoerythrocytic stages of the human malaria parasite Plasmodium malariae. Am. J. Trop. Med. Hyg. 38, 470–473 (1988).

    Article  CAS  PubMed  Google Scholar 

  63. Millet, P. G. et al. In vitro cultivation of Plasmodium cynomolgi bastianelli in hepatocytes of the Macaca rhesus. Ann. Parasitol. Hum. Comp. 62, 5–7 (1987) (in French).

    Article  CAS  PubMed  Google Scholar 

  64. Millet, P. G., Fisk, T. L., Collins, W. E., Broderson, J. R. & Nguyen-Dinh, P. Cultivation of exoerythrocytic stages of Plasmodium cynomolgi, P. knowlesi, P. coatneyi, and P. inui in Macaca mulatta hepatocytes. Am. J. Trop. Med. Hyg. 39, 529–534 (1988).

    Article  CAS  PubMed  Google Scholar 

  65. Karnasuta, C. et al. Complete development of the liver stage of Plasmodium falciparum in a human hepatoma cell line. Am. J. Trop. Med. Hyg. 53, 607–611 (1995).

    Article  CAS  PubMed  Google Scholar 

  66. Sattabongkot, J. et al. Establishment of a human hepatocyte line that supports in vitro development of the exo-erythrocytic stages of the malaria parasites Plasmodium falciparum and P. vivax. Am. J. Trop. Med. Hyg. 74, 708–715 (2006).

    Article  CAS  PubMed  Google Scholar 

  67. Prudencio, M., Rodriguez, A. & Mota, M. M. The silent path to thousands of merozoites: the Plasmodium liver stage. Nature Rev. Microbiol. 4, 849–856 (2006).

    Article  CAS  Google Scholar 

  68. Calvo-Calle, J. M., Moreno, A., Eling, W. M. C. & Nardin, E. H. In vitro development of infectious liver stages of P. yoelii and P. berghei malaria in human cell lines. Exp. Parasitol. 79, 362–373 (1994).

    Article  CAS  PubMed  Google Scholar 

  69. Hollingdale, M. R. Malaria and the liver. Hepatology 5, 327–335 (1985).

    Article  CAS  PubMed  Google Scholar 

  70. Silvie, O. et al. Expression of human CD81 differently affects host cell susceptibility to malaria sporozoites depending on the Plasmodium species. Cell. Microbiol. 8, 1134–1146 (2006).

    Article  CAS  PubMed  Google Scholar 

  71. Hollingdale, M. R., Collins, W. E., Campbell, C. C. & Schwartz, A. L. In vitro culture of two populations (dividing and nondividing) of exoerythrocytic parasites of Plasmodium vivax. Am. J. Trop. Med. Hyg. 34, 216–222 (1985).

    Article  CAS  PubMed  Google Scholar 

  72. Hollingdale, M. R., Collins, W. E. & Campbell, C. C. In vitro culture of exoerythrocytic parasites of the North Korean strain of Plasmodium vivax in hepatoma cells. Am. J. Trop. Med. Hyg. 35, 275–276 (1986).

    Article  CAS  PubMed  Google Scholar 

  73. Silvie, O. et al. A role for apical membrane antigen 1 during invasion of hepatocytes by Plasmodium falciparum sporozoites. J. Biol. Chem. 279, 9490–9406 (2004).

    Article  CAS  PubMed  Google Scholar 

  74. Meis, J. F. et al. Infection of cryopreserved adult human hepatocytes with Plasmodium falciparum sporozoites. Cell Biol. Int. Rep. 9, 976 (1985).

    Article  CAS  PubMed  Google Scholar 

  75. Rénia, L. et al. Malaria sporozoite penetration. A new approach by double staining. J. Immunol. Methods 112, 201–205 (1988).

    Article  PubMed  Google Scholar 

  76. Mazier, D. et al. Effect of antibodies to recombinant and synthetic peptides on P. falciparum sporozoites in vitro. Science 231, 156–159 (1986).

    Article  CAS  PubMed  Google Scholar 

  77. Gego, A. et al. New approach for high-throughput screening of drug activity on Plasmodium liver stages. Antimicrob. Agents Chemother. 50, 1586–1589 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Rodrigues, C. D. et al. Host scavenger receptor SR-BI plays a dual role in the establishment of malaria parasite liver infection. Cell Host Microbe 4, 271–282 (2008).

    Article  CAS  PubMed  Google Scholar 

  79. Prudencio, M., Rodrigues, C. D., Ataide, R. & Mota, M. M. Dissecting in vitro host cell infection by Plasmodium sporozoites using flow cytometry. Cell. Microbiol. 10, 218–224 (2008).

    CAS  PubMed  Google Scholar 

  80. Jung, M. et al. Effects of hepatocellular iron imbalance on nitric oxide and reactive oxygen intermediates production in a model of sepsis. J. Hepatol. 33, 387–394 (2000).

    Article  CAS  PubMed  Google Scholar 

  81. Yalaoui, S. et al. Hepatocyte permissiveness to Plasmodium infection is conveyed by a short and structurally conserved region of the CD81 large extracellular domain. PLoS Pathogen 4, e1000010 (2008).

    Article  CAS  Google Scholar 

  82. Most, H., Herman, R. H. & Schoenfeld, C. Chemotherapy of sporozoite- and blood-induced Plasmodium berghei infections with selected antimalarial agents. Am. J. Trop. Med. Hyg. 16, 572–575 (1967).

    Article  CAS  PubMed  Google Scholar 

  83. Fink, E. Assessment of causal prophylactic activity in Plasmodium berghei yoelii and its value for the development of new antimalarial drugs. Bull. World Health Organ. 50, 213–222 (1974).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Hulier, E. et al. A method for the quantitative assessment of malaria parasite development in organs of the mammalian host. Mol. Biochem. Parasitol. 77, 127–135 (1996).

    Article  CAS  PubMed  Google Scholar 

  85. Briones, M. R. S., Tsuji, M. & Nussenzweig, V. The large difference in infectivity for mice of Plasmodium berghei and Plasmodium yoelii sporozoites cannot be correlated with their ability to enter into hepatocytes. Mol. Biochem. Parasitol. 77, 7–17 (1996).

    Article  CAS  PubMed  Google Scholar 

  86. Bruña-Romero, O. et al. Detection of malaria liver-stages in mice infected through the bite of a single Anopheles mosquito using a highly sensitive real-time PCR. Int. J. Parasitol. 31, 1499–1502 (2001).

    Article  PubMed  Google Scholar 

  87. Witney, A. A. et al. Determining liver stage parasite burden by real time quantitative PCR as a method for evaluating pre-erythrocytic malaria vaccine efficacy. Mol. Biochem. Parasitol. 118, 233–245 (2001).

    Article  CAS  PubMed  Google Scholar 

  88. Snounou, G., Grüner, A. C., Müller-Graf, C. D., Mazier, D. & Rénia, L. The Plasmodium sporozoite survives RTS,S vaccination. Trends Parasitol. 21, 456–461 (2005).

    Article  CAS  PubMed  Google Scholar 

  89. Carraz, M. et al. A plant-derived morphinan as a novel lead compound active against malaria liver stages. PLoS Medicine 3, e513 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Grüner, A. C. et al. Insights into the P. y. yoelii hepatic stage transcriptome reveal complex transcriptional patterns. Mol. Biochem. Parasitol. 142, 184–192 (2005).

    Article  PubMed  CAS  Google Scholar 

  91. Sacci, J. B. Jr, Aguiar, J. C., Lau, A. O. T. & Hoffman, S. L. Laser capture microdissection and molecular analysis of Plasmodium yoelii liver-stage parasites. Mol. Biochem. Parasitol. 119, 285–289 (2002).

    Article  CAS  PubMed  Google Scholar 

  92. Semblat, J.-P. et al. Laser capture microdissection of Plasmodium falciparum liver stages for mRNA analysis. Mol. Biochem. Parasitol. 121, 179–183 (2002).

    Article  CAS  PubMed  Google Scholar 

  93. Siau, A. et al. Temperature shift and host cell contact up-regulate sporozoite expression of Plasmodium falciparum genes involved in hepatocyte infection. PLoS Pathogen 4, e1000121 (2008).

    Article  CAS  Google Scholar 

  94. Tarun, A. S. et al. A combined transcriptome and proteome survey of malaria parasite liver stages. Proc. Natl Acad. Sci. USA 105, 305–310 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Cunha-Rodrigues, M., Prudencio, M., Mota, M. M. & Haas, W. Antimalarial drugs — host targets (re)visited. Biotechnol. J. 1, 321–332 (2006).

    Article  CAS  PubMed  Google Scholar 

  96. Mahmoudi, N. et al. New active drugs against liver stages of Plasmodium predicted by molecular topology. Antimicrob. Agents Chemother. 52, 1215–1220 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Doerig, C. & Meijer, L. Antimalarial drug discovery: targeting protein kinases. Exp. Opin. Ther. Targets 11, 279–290 (2007).

    Article  Google Scholar 

  98. Edgcomb, J. H., Arnold, J. D., Yount, E. H. Jr, Alving, A. S. & Eichelberger, L. Primaquine, SN 13272, a new curative agent in vivax malaria: a preliminary report. J. Natl Malaria Soc. 9, 285–292 (1950).

    CAS  Google Scholar 

  99. Hill, D. R. et al. Primaquine: report from CDC expert meeting on malaria chemoprophylaxis I. Am. J. Trop. Med. Hyg. 75, 402–415 (2006).

    Article  CAS  PubMed  Google Scholar 

  100. Baird, J. K., Fryauff, D. J. & Hoffman, S. L. Primaquine for prevention of malaria in travelers. Clin. Infect. Dis. 37, 1659–1667 (2003).

    Article  CAS  PubMed  Google Scholar 

  101. Peters, W. The evolution of tafenoquine — antimalarial for a new millennium? J. Royal Soc. Med. 92, 345–352 (1999).

    Article  CAS  Google Scholar 

  102. Brueckner, R. P., Coster, T., Wesche, D. L., Shmuklarsky, M. J. & Schuster, B. G. Prophylaxis of Plasmodium falciparum infection in a human challenge model with WR 238605, a new 8-aminoquinoline antimalarial. Antimicrob. Agents Chemother. 42, 1293–1294 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Dutta, G. P., Puri, S. K., Bhaduri, A. P. & Seth, M. Radical curative activity of a new 8-aminoquinoline derivative (CDRI 80/53) against Plasmodium cynomolgi B in monkeys. Am. J. Trop. Med. Hyg. 41, 635–637 (1989).

    Article  CAS  PubMed  Google Scholar 

  104. Krudsood, S. et al. Safety and tolerability of elubaquine (bulaquine, CDRI 80/53) for treatment of Plasmodium vivax malaria in Thailand. Korean J. Parasitol. 44, 221–228 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Valecha, N. et al. Comparative antirelapse efficacy of CDRI compound 90/53 (Bulaquine) vs primaquine in double blind clinical trials. Curr. Sci. 80, 561–563 (2001).

    CAS  Google Scholar 

  106. Alving, A. S. et al. Potentiation of the curative action of primaquine in vivax malaria by quinine and chloroquine. J. Lab. Clin. Med. 46, 301–306 (1955).

    CAS  PubMed  Google Scholar 

  107. Schmidt, L. H., Fradkin, R., Vaughan, D. & Rasco, J. Radical cure of infections with Plasmodium cynomolgi: a function of total 8-aminoquinoline dose. Am. J. Trop. Med. Hyg. 26, 1116–1128 (1977).

    Article  CAS  PubMed  Google Scholar 

  108. Alving, A. S. et al. Korean vivax malaria. II. Curative treatment with pamaquine and primaquine. Am. J. Trop. Med. Hyg. 2, 970–976 (1953).

    Article  CAS  PubMed  Google Scholar 

  109. Arnold, J. D., Alving, A. S. & Clayman, C. B. Induced primaquine resistance in vivax malaria. Trans. Royal Soc. Trop. Med. Hyg. 55, 345–350 (1961).

    Article  CAS  Google Scholar 

  110. Singh, N. & Puri, S. K. Causal prophylactic activity of antihistaminic agents against Plasmodium yoelii nigeriensis infection in Swiss mice. Acta Trop. 69, 255–260 (1998).

    Article  CAS  PubMed  Google Scholar 

  111. Singh, N. & Puri, S. K. Inhibition of the development of the hepatic stages of Plasmodium yoelii nigeriensis by antihistaminic agents. Ann. Trop. Med. Parasitol. 93, 419–422 (1999).

    Article  CAS  PubMed  Google Scholar 

  112. Zhang, Q. et al. Unambiguous synthesis and prophylactic antimalarial activities of imidazolidinedione derivatives. J. Med. Chem. 48, 6472–6481 (2005).

    Article  CAS  PubMed  Google Scholar 

  113. Coppi, A. et al. Heparan sulfate proteoglycans provide a signal to Plasmodium sporozoites to stop migrating and productively invade host cells. Cell Host Microbe 2, 316–327 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Bosch, J. et al. Aldolase provides an unusual binding site for thrombospondin-related anonymous protein in the invasion machinery of the malaria parasite. Proc. Natl Acad. Sci. USA 104, 7015–7020 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Coppi, A., Pinzon-Ortiz, C., Hutter, C. & Sinnis, P. The Plasmodium circumsporozoite protein is proteolytically processed during cell invasion. J. Exp. Med. 201, 27–33 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Talati, S. M., Latham, M. R., Moore, E. G., Hargreaves, G. W. & DeWitt Blanton, C. Jr. Synthesis of potential antimalarials: primaquine analogs. J. Pharm. Sci. 59, 491–495 (1970).

    Article  CAS  PubMed  Google Scholar 

  117. Li, J. et al. Plasmodium berghei: quantitation of in vitro effects of antimalarial drugs on exoerythrocytic development by a ribosomal RNA probe. Exp. Parasitol. 72, 450–458 (1991).

    Article  CAS  PubMed  Google Scholar 

  118. Powell, R. D. & Brewer, G. J. Effects of pyrimethamine, chlorguanide, and primaquine against exoerythrocytic forms of a strain of chloroquine-resistant Plasmodium falciparum from Thailand. Am. J. Trop. Med. Hyg. 16, 693–698 (1967).

    Article  CAS  PubMed  Google Scholar 

  119. Nduati, E. et al. Effect of folate derivatives on the activity of antifolate drugs used against malaria and cancer. Parasitol. Res. 102, 1227–1234 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Gregory, K. G. & Peters, W. The chemotherapy of rodent malaria. IX. Causal prophylaxis. I. A method for demonstrating drug action on exo-erythrocytic stages. Ann. Trop. Med. Parasitol. 64, 15–24 (1970).

    Article  CAS  PubMed  Google Scholar 

  121. Hollingdale, M. R., McCann, P. P. & Sjoerdsma, A. Plasmodium berghei: inhibitors of ornithine decarboxylase block exoerythrocytic schizogony. Exp. Parasitol. 60, 111–117 (1985).

    Article  CAS  PubMed  Google Scholar 

  122. Gantt, S. M. et al. Proteasome inhibitors block development of Plasmodium spp. Antimicrob. Agents Chemother. 42, 2731–2738 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Davies, C. S., Pudney, M., Nicholas, J. C. & Sinden, R. E. The novel hydroxynaphthoquinone 566C80 inhibits the development of liver stages of Plasmodium berghei cultured in vitro. Parasitology 106, 1–6 (1993).

    Article  CAS  PubMed  Google Scholar 

  124. Andersen, S. L. et al. Efficacy of azithromycin as a causal prophylactic agent against murine malaria. Antimicrob. Agents Chemother. 38, 1862–1863 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Marussig, M. S. et al. Activity of doxycycline against preerythrocytic malaria. J. Infect. Dis. 168, 1603–1604 (1993).

    Article  CAS  PubMed  Google Scholar 

  126. Mahmoudi, N. et al. In vitro activities of 25 quinolones and fluoroquinolones against liver and blood stage Plasmodium spp. Antimicrob. Agents Chemother. 47, 2636–2639 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Yu, M. et al. The fatty acid biosynthesis enzyme FabI plays a key role in the development of liver-stage malarial parasites. Cell Host Microbe 4, 567–578 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Vaughan, A. M. et al. Type II fatty acid synthesis is essential only for malaria parasite late liver stage development. Cell. Microbiol. 11, 506–520 (2009).

    Article  CAS  PubMed  Google Scholar 

  129. Van De Sand, C. et al. The liver stage of Plasmodium berghei inhibits host cell apoptosis. Mol. Microbiol. 58, 731–742 (2005).

    Article  CAS  PubMed  Google Scholar 

  130. Sturm, A. et al. Manipulation of host hepatocytes by the malaria parasite for delivery into liver sinusoids. Science 313, 1287–1290 (2006).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to A. C. Grüner for critical reading of the manuscript and many helpful and pertinent suggestions. D.M., L.R. and G.S. are currently part of an official collaboration between SIgN-/A*-STAR and INSERM (Laboratoire International Associé, INSERM).

Author information

Author notes

  1. Dominique Mazier, Laurent Rénia and Georges Snounou: All authors contributed equally to this work.

Authors and Affiliations

  1. Dominique Mazier and Georges Snounou are at the Institut National de la Santé et de la Recherche Médicale U945, F-75013 Paris, France; and at Université Pierre et Marie Curie, Faculté de Médecine Pitié-Salpêtrière, F-75013 Paris, France.,

    Dominique Mazier & Georges Snounou

  2. and at Université Pierre et Marie Curie, Faculté de Médecine Pitié-Salpêtrière, F-75013 Paris, France.,

    Dominique Mazier & Georges Snounou

  3. Dominique Mazier is also at the Assistance Publique Hôpitaux de Paris, Centre Hospitalo-Universitaire Pitié-Salpêtrière, F-75013 Paris, France.,

    Dominique Mazier

  4. Laurent Rénia is at the Singapore Immunology Network, A*STAR, Biopolis, Singapore.,

    Laurent Rénia

  5. Laurent Rénia and Georges Snounou are also at the Department of Microbiology, National University of Singapore, 5 Science Drive 2 Singapore 117597, Singapore.,

    Laurent Rénia & Georges Snounou

Authors
  1. Dominique Mazier
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laurent Rénia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Georges Snounou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dominique Mazier.

Supplementary information

Supplementary information S1 (table)

Compounds with known anti-LS activity (PDF 625 kb)

Related links

Related links

FURTHER INFORMATION

Dominique Mazier's homepage

Laurent Rénia's homepage

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mazier, D., Rénia, L. & Snounou, G. A pre-emptive strike against malaria's stealthy hepatic forms. Nat Rev Drug Discov 8, 854–864 (2009). https://doi.org/10.1038/nrd2960

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd2960

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing