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Hemozoin Biocrystallization in Plasmodium falciparum and the antimalarial activity of crystallization inhibitors

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References

  • Atamna H, Krugliak M, Shalmiev G, Deharo E, Pescarmona G, Ginsburg H (1996) Mode of antimalarial effect of methylene blue and some of its analoques on Plasmodium falciparum in culture and their inhibition of P. vinckei petteri and P. yoelli nigeriensis in vivo. Biochem Pharmacol 51:693–700

    PubMed  Article  CAS  Google Scholar 

  • Ball EG, McKee RW, Anfinsen CB, Cruz WO, Geiman QM (1948) Studies on malarial parasites. IX. Chemical and metabolic changes during growth and multiplication in vivo and in vitro. J Biol Chem 175:547–571

    CAS  Google Scholar 

  • Bäuerlein E (ed) (2004) Biomineralization. Wiley-VCH Verlag GmbH, Weinheim

    Google Scholar 

  • Bray PG, Mungthin M, Ridley RG, Ward SA (1998) Access to hematin: the basis of chloroquine resistance. Mol Pharmacol 54:170–179

    PubMed  CAS  Google Scholar 

  • Bray PG, Ward SA, O’Neill PM (2005) Quinolines and artemisinin: chemistry, biology and history. Curr Top Microbiol Immunol 295:3–38

    PubMed  CAS  Google Scholar 

  • Brown WH (1911) Malarial pigment (so-called melanin): its nature and mode of production. J Exp Med 13:290–300

    Article  CAS  Google Scholar 

  • Carbone T (1891) Sulla natura chimica del pigmento malarico. G R Accad Med Torino 39:901–906

    Google Scholar 

  • Chong CR, Sullivan DJ (2003) Inhibition of heme crystal growth by antimalarials and other compounds: implication for drug discovery. Biochem Pharmacol 66:2201–2212

    PubMed  Article  CAS  Google Scholar 

  • Coatney GR (1963) Pitfalls in a discovery: the chronicle of chloroquine. Am J Trop Med Hyg 12:121–128

    PubMed  CAS  Google Scholar 

  • Dascombe MJ, Drew MG, Morris H, Wilairat P, Auparakkitanon S, Moule WA, Alizadeh-Shekalgourabi S, Evans PG, Lloyd M, Dyas AM, Carr P, Ismail FM (2005) Mapping antimalarial pharmacophores as a useful tool for the rapid discovery of drugs effective in vivo: design, construction, characterization, and pharmacology of metaquine. J Med Chem 48:5423–5436

    PubMed  Article  CAS  Google Scholar 

  • Deegan T, Maegraith BG (1956) Studies on the nature of malarial pigment (hemozoin). Ann Trop Med Parasitol 50:194–211

    PubMed  CAS  Google Scholar 

  • Deharo E, Garcia RN, Oporto P, Gimenez A, Sauvain M, Jullian V, Ginsburg H (2002) A non-radiolabelled ferriprotoporphyrin IX biomineralisation inhibition test for the high throughput screening of antimalarial compounds. Exp Parasitol 100:252–2566

    PubMed  Article  CAS  Google Scholar 

  • Dünschede H-B (1971) Tropenmedizinische Forschung bei Bayer. Michael Triltsch Verlag, Düsseldorf

    Google Scholar 

  • Egan TJ (2002) Physico-chemical aspects of hemozoin (malaria pigment) structure and formation. J Inorg Biochem 91:19–26

    PubMed  Article  CAS  Google Scholar 

  • Egan TJ (2006) Interactions of quinoline antimalarials with hematin in solution. J Inorg Biochem 100:916–926

    PubMed  Article  CAS  Google Scholar 

  • Egan TJ, Hempelmann E, Mavuso WW (1999) Characterisation of synthetic beta-haematin and effects of the antimalarial drugs quinidine, halofantrine, desbutylhalofantrine and mefloquine on its formation. J Inorg Biochem 73:101–107

    PubMed  Article  CAS  Google Scholar 

  • Egan TJ, Mavuso WW, Ncokazi KK (2001) The mechanism of beta-hematin formation in acetate solution. Parallels between hemozoin formation and biomineralization processes. Biochemistry 40:204–213

    PubMed  Article  CAS  Google Scholar 

  • Ezzet F, van Vugt M, Nosten F, Looareesuwan S, White NJ (2000) Pharmacokinetics and pharmacodynamics of lumefantrine (benflumetol) in acute falciparum malaria. Antimicrob Agents Chemother 44:697–704

    PubMed  Article  CAS  Google Scholar 

  • Fitch CD (2004) Ferriprotoporphyrin IX, phospholipids, and the antimalarial actions of quinoline drugs. Life Sci 74:1957–1972

    PubMed  Article  CAS  Google Scholar 

  • Fitch CD, Kanjananggulpan P (1987) The state of ferriprotoporphyrin IX in malaria pigment. J Biol Chem 262:15552–15555

    PubMed  CAS  Google Scholar 

  • Frerichs FT (1858) Pathologisch-anatomischer Atlas zur Klinik der Leberkrankheiten Band I: Klinik der Leberkrankheiten, Kapitel VIII Die Pigmentleber. Melanämische Leber. Veränderungen der Leber bei Intermittens. 325–368, F. Vieweg und Sohn, Braunschweig

  • Guttmann P, Ehrlich P (1891) Ueber die Wirkung desMethylenblau bei Malaria. Berliner Klinische Wochenschrift 39:953–956

    Google Scholar 

  • Hamsik A (1925) Zur Darstellung des Oxyhämins. Hoppe-Seyler Z Physiol Chem 148:99–110

    CAS  Google Scholar 

  • Harinasuta T, Migasen S, Bunnag D (1962) Chloroquine resistance in Plasmodium falciparum in Thailand. In: UNESCO First Regional Symposium on Scientific Knowledge of Tropical Parasites pp. 148–153, University of Singapore, Singapore

  • Hempelmann E, Egan TJ (2002) Pigment biocrystallization in Plasmodium falciparum. Trends Parasitol 18:11

    PubMed  Article  Google Scholar 

  • Hempelmann E, Marques HM (1994) Analysis of malaria pigment from Plasmodium falciparum. J Pharmacol Toxicol Methods 32:25–30

    PubMed  Article  CAS  Google Scholar 

  • Hempelmann E, Motta C, Hughes R, Ward SA, Bray PG (2003) Plasmodium falciparum: sacrificing membrane to grow crystals? Trends Parasitol 19:23–26

    PubMed  Article  CAS  Google Scholar 

  • Homewood CA, Moore GA, Warhurst DC, Atkinson EM (1975) Purification and some properties of malarial pigment. Ann Trop Med Parasitol 69:283–287

    PubMed  CAS  Google Scholar 

  • Kaufman TS, Ruveda EA (2005) The quest for quinine: those who won the battles and those who won the war. Angew Chem Int Ed 44:854–885

    Article  CAS  Google Scholar 

  • Laveran CLA (1880) A newly discovered parasite in the blood of patients suffering from malaria. Parasitic etiology of attacks of malaria. Translated from the French and reprinted. In: Kean BH, Mott KE, Russell AJ (eds) Tropical Medicine and Parasitology. Classic Investigations. Vol. 1, 1978: Cornell University Press, Ithaca, New York

    Google Scholar 

  • Leed A, DuBay K, Ursos LM, Sears D, De Dios AC, Roepe PD (2002) Solution structures of antimalarial drug–heme complexes. Biochemistry 41:10245–10255

    PubMed  Article  CAS  Google Scholar 

  • Lemberg R, Legge JW (1949) Hematin compounds and bile pigments. Interscience, New York

    Google Scholar 

  • Lew VL, Tiffert T, Ginsburg H (2003) Excess hemoglobin digestion and the osmotic stability of Plasmodium falciparum infected red blood cells. Blood 101:4189–4194

    PubMed  Article  CAS  Google Scholar 

  • Lowenstam HA, Weiner S (1989) On biomineralization. Oxford University Press, New York

    Google Scholar 

  • Macomber PB, Sprinz H, Tousimis AJ (1967) Morphological effects of chloroquine on Plasmodium berghei in mice. Nature 214:937–939

    PubMed  Article  CAS  Google Scholar 

  • Mann S (2002) Biomineralization. Oxford University Press, New York

    Google Scholar 

  • Meckel H (1847) Ueber schwarzes Pigment in der Milz und dem Blute einer Geisteskranken. Zeitschr f Psychiatrie IV:198–226

    Google Scholar 

  • Moore DV, Lanier JE (1961) Observations on two Plasmodium falciparum infections with an abnormal response to chloroquine. Am J Trop Med Hyg 10:5–9

    PubMed  CAS  Google Scholar 

  • Omodeo-Sale F, Motti A, Dondorp A, White NJ, Taramelli D (2005) Destabilisation and subsequent lysis of human erythrocytes induced by Plasmodium falciparum haem products. Eur J Haematol 74:324–332

    PubMed  Article  CAS  Google Scholar 

  • Pagola S, Stephens PW, Bohle DS, Kosar AD, Madsen SK (2000) The structure of malaria pigment beta-haematin. Nature 404:307–310

    PubMed  Article  CAS  Google Scholar 

  • Peters W (1964) Pigment formation and nuclear division in chloroquine-resistant malaria parasites (Plasmodium berghei, Vincke and Lips, 1948). Nature 203:1290–1291

    PubMed  Article  CAS  Google Scholar 

  • Scholl PF, Tripathi AK, Sullivan DJ (2005) Bioavailable iron and heme metabolism in Plasmodium falciparum. Curr Top Microbiol Immunol 295:293–324

    PubMed  CAS  Article  Google Scholar 

  • Schulemann W (1932) Synthetic anti-malarial preparations. Proc R Soc Med 25:897–905

    Google Scholar 

  • Sharma V (2005) Therapeutic drugs for targeting chloroquine resistance in malaria. Mini-Reviews in Medical Chemistry 5:337–351

    Article  CAS  Google Scholar 

  • Slater AFG, Cerami A (1992) Inhibition by chloroquine of a novel haem polymerase enzyme activity in malaria trophozoites. Nature 355:167–169

    PubMed  Article  CAS  Google Scholar 

  • Slater AFG, Swiggard WJ, Orton BR, Flitter WD, Goldberg DE, Cerami A, Henderson GB (1991) An iron-carboxylate bond links the heme units of malaria pigment. PNAS 88:325–329

    PubMed  Article  CAS  Google Scholar 

  • Smith DC, Sanford LB (1985) Laveran’s germ: the reception and use of a medical discovery. Am J Trop Med Hyg 34:2–20

    PubMed  CAS  Google Scholar 

  • Sullivan DJ (2002) Hemozoin, a biocrystal synthesized during the degradation of hemoglobin. In: Matsumura S, Steinbüchel A (eds) Biopolymers, vol. 9, Wiley-VCH Verlag GmbH, Weinheim pp 129–163

    Google Scholar 

  • Tekwani BL, Walker LA (2005) Targeting the hemozoin synthesis pathway for new antimalarial drug discovery: technologies for in vitro β-hematin formation assay. Comb Chem High Throughput Screen 8:61–67

    Article  Google Scholar 

  • Vennerstrom JL, Makler MT, Angerhofer CK, William JA (1995) Antimalarial dyes revisited: xanthenes, azines, oxazines and thiazines. Antimicrob Agents Chemother 39:2671–2677

    PubMed  CAS  Google Scholar 

  • Virchow R (1849) Zur pathologischen Physiologie des Blutes. Arch Pathol Anatomie 2:587–598

    Article  Google Scholar 

  • Wainwright M, Amaral L (2005) The phenothiazinium chromophore and the evolution of antimalarial drugs. Trop Med Int Health 10:501–511

    PubMed  Article  CAS  Google Scholar 

  • Warhurst DC, Hockley DJ (1967) Mode of action of chloroquine on Plasmodium berghei and P. cynomolgi. Nature 214:935–936

    PubMed  Article  CAS  Google Scholar 

  • Warhurst DC, Craig JC, Adagu IS, Meyer DJ, Lee SY (2003) The relationship of physico-chemical properties and structure of the differential antiplasmodial activity of the cinchona alkaloids. Malar J 2:26

    PubMed  Article  Google Scholar 

  • Wellems TE, Plowe CV (2001) Chloroquine-resistant malaria. J Infect Dis 184:770–776

    PubMed  Article  CAS  Google Scholar 

  • Woodward RB, Doering WE (1945) The total synthesis of quinine. J Am Chem Soc 67:860–874

    Article  CAS  Google Scholar 

  • Ziegler J, Linck R, Wright DW (2001) Heme aggregation inhibitors: antimalarial drugs targeting an essential biomineralization process. Curr Med Chem 8:171–189

    PubMed  CAS  Google Scholar 

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Acknowledgements

Electron micrographs (Figs. 3 and 4) were imaged by Lawrence Bannister and John Hopkins, Department of Anatomy and Human Science, Guy’s, King’s and St Thomas’ Medical School, London. The freeze fracture replica was prepared by Anthony Brain, Centre for Ultrastructural Imaging, King’s College London. The advice and support of Graham H. Mitchell, Guy’s Hospital London, is gratefully acknowledged.

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Hempelmann, E. Hemozoin Biocrystallization in Plasmodium falciparum and the antimalarial activity of crystallization inhibitors. Parasitol Res 100, 671–676 (2007). https://doi.org/10.1007/s00436-006-0313-x

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Keywords

  • Malaria
  • Methylene Blue
  • Chloroquine
  • Antimalarial Drug
  • Halofantrine