Journal of Pharmacopuncture (대한약침학회지)

KOREAN PHARMACOPUNCTURE INSTITUTE (대한약침학회)
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Anti-malarial Drug Design by Targeting Apicoplasts: New Perspectives

  • Received : 2015.11.06
  • Accepted : 2016.01.13
  • Published : 2016.03.31
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Abstract

Objectives: Malaria has been a major global health problem in recent times with increasing mortality. Current treatment methods include parasiticidal drugs and vaccinations. However, resistance among malarial parasites to the existing drugs has emerged as a significant area of concern in anti-malarial drug design. Researchers are now desperately looking for new targets to develop anti-malarials drug which is more target specific. Malarial parasites harbor a plastid-like organelle known as the 'apicoplast', which is thought to provide an exciting new outlook for the development of drugs to be used against the parasite. This review elaborates on the current state of development of novel compounds targeted againstemerging malaria parasites. Methods: The apicoplast, originates by an endosymbiotic process, contains a range of metabolic pathways and housekeeping processes that differ from the host body and thereby presents ideal strategies for anti-malarial drug therapy. Drugs are designed by targeting the unique mechanism of the apicoplasts genetic machinery. Several anabolic and catabolic processes, like fatty acid, isopenetyl diphosphate and heme synthess in this organelle, have also been targeted by drugs. Results: Apicoplasts offer exciting opportunities for the development of malarial treatment specific drugs have been found to act by disrupting this organelle's function, which wouldimpede the survival of the parasite. Conclusion: Recent advanced drugs, their modes of action, and their advantages in the treatment of malaria by using apicoplasts as a target are discussed in this review which thought to be very useful in desigining anti-malarial drugs. Targetting the genetic machinery of apicoplast shows a great advantange regarding anti-malarial drug design. Critical knowledge of these new drugs would give a healthier understanding for deciphering the mechanism of action of anti-malarial drugs when targeting apicoplasts to overcome drug resistance.

Keywords

References

  1. World Health Organization. World Malaria Report 2015 [internet]. India: World Health Organization; 2015 [Cited by 2015]. Available from: http://www.who.int/wer/2015/wer9045.pdf.
  2. Hayton K, Su XZ. Drug resistance and genetic mapping in Plasmodium falciparum. Curr Genet. 2008;54(5):223-39. https://doi.org/10.1007/s00294-008-0214-x
  3. Gleeson MT. The plastid in Apicomplexa: what use is it?. Int J Parasitol. 2000;30(10):1053-70. https://doi.org/10.1016/S0020-7519(00)00100-4
  4. Bouchut A, Geiger JA, Derocher AE, Parsons M. Vesicles bearing Toxoplasma apicoplast membrane proteins persist following loss of the relict plastid or Golgi body disruption. PLoS One. 2014;9(11):e112096. https://doi.org/10.1371/journal.pone.0112096
  5. Kalanon M, McFadden GI. Malaria, Plasmodium falciparum and its apicoplast. Biochem Soc Trans. 2010;38(3):775-82. https://doi.org/10.1042/BST0380775
  6. Ralph SA, van Dooren GG, Waller RF, Crawford MJ, Fraunholz MJ, Foth BJ, et al. Tropical infectious diseases: metabolic maps and functions of the Plasmodium falciparum apicoplast. Nat Rev Microbiol. 2004;2(3):203-16. https://doi.org/10.1038/nrmicro843
  7. White NJ. Antimalarial drug resistance. J Clin Invest. 2004;113(8):1084-92. https://doi.org/10.1172/JCI21682
  8. Cowman AF, Galatis D, Thompson JK. Selection for mefloquine resistance in Plasmodium falciparum is linked to amplification of the pfmdr1 gene and cross-resistance to halofantrine and quinine. Proc Natl Acad Sci USA. 2004;91(3):1143-7.
  9. Plowe CV. Monitoring antimalarial drug resistance making the most of the tools at hand. J Exp Biol. 2003;206(21):3745-52. https://doi.org/10.1242/jeb.00658
  10. Arisue N, Hashimoto T. Phylogeny and evolution of apicoplasts and apicomplexan parasites. Parasitol Int. 2015;64(3):254-9. https://doi.org/10.1016/j.parint.2014.10.005
  11. Miotto O, Amato R, Ashley EA, MacInnis B, Almagro-Garcia J, Amaratunga C, et al. Genetic architecture of artemisinin-resistant Plasmodium falciparum. Nat Genet. 2015;47(3):226-34. https://doi.org/10.1038/ng.3189
  12. Chandey M, Mannan R, Bhasin TS, Manjari M. Quinine-resistant severe falciparum malaria in north India: documentation. Indian Journal of Medical Specialities. 2013;4(1):99-102.
  13. Awab GR, Pukrittayakamee S, Imwong M, Dondorp AM, Woodrow CJ, Lee SJ, et al. Dihydroartemisinin-piperaquine versus chloroquine to treat vivax malaria in Afghanistan: an open randomized, non-inferiority, trial. Malar J. 2010;9:105. https://doi.org/10.1186/1475-2875-9-105
  14. Farooq U, Mahajan RC. Drug resistance in malaria. J Vector Borne Dis. 2004;41(3-4):45-53.
  15. Eastman RT, Dharia NV, Winzeler EA, Fidock DA. Piperaquine resistance is associated with a copy number variation on chromosome 5 in drug-pressured Plasmodium falciparum parasites. Antimicrob Agents Chemother. 2011;55(8):3908-16. https://doi.org/10.1128/AAC.01793-10
  16. Barnes KI, Little F, Smith PJ, Evans A, Watkins WM, White NJ. Sulfadoxine-pyrimethamine pharmacokinetics in malaria: pediatric dosing implications. Clin Pharmacol Ther. 2006;80(6):582-96. https://doi.org/10.1016/j.clpt.2006.08.016
  17. Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, et al. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2009;361(5):455-67. https://doi.org/10.1056/NEJMoa0808859
  18. Imwong M, Dondorp AM, Nosten F, Yi P, Mungthin M, Hanchana S, et al. Exploring the contribution of candidate genes to artemisinin resistance in Plasmodium falciparum. Antimicrob Agents Chemother. 2010;54(7):2886-92. https://doi.org/10.1128/AAC.00032-10
  19. Heuchert A, Abduselam N, Zeynudin A, Eshetu T, Loscher T, Wieser A, et al. Molecular markers of anti-malarial drug resistance in southwest Ethiopia over time: regional surveillance from 2006 to 2013. Malar J. 2015;14:208. https://doi.org/10.1186/s12936-015-0723-2
  20. Liting L, Geoffrey IM. The evolution, metabolism and functions of the apicoplast. Philos Trans R Soc Lond B Biol Sci. 2010;365(1541):749-63. https://doi.org/10.1098/rstb.2009.0273
  21. Macrae JI, Marechal E, Biot C, Botte CY. The apicoplast: a key target to cure malaria. Curr Pharm Des. 2012;18(24):3490-504.
  22. Stuart A. Ralph, Marthe C. D'Ombrain, Geoffrey I. Mc-Fadden. The apicoplast as an antimalarial drug target. Drug Resistance Updates. 2001;4(3):145-51. https://doi.org/10.1054/drup.2001.0205
  23. Abrahamsen MS, Templeton TJ, Enomoto S, Abrahante JE, Zhu G, Lancto CA, et al. Complete genome sequence of the apicomplexan, Cryptosporidium parvum. Science. 2004;304(5669):441-5. https://doi.org/10.1126/science.1094786
  24. Moore RB, Obornik M, Janouskovec J, Chrudimsky T, Vancova M, Green DH, et al. A photosynthetic alveolate closely related to apicomplexan parasites. Nature. 2008;451(7181):959-63. https://doi.org/10.1038/nature06635
  25. Dar MA, Sharma A, Mondal N, Dhar SK. Molecular cloning of apicoplast-targeted Plasmodium falciparum DNA gyrase genes: unique intrinsic ATPase activity and ATP-independent dimerization of PfGyrB subunit. Eukaryot Cell. 2007;6(3):398-412. https://doi.org/10.1128/EC.00357-06
  26. Raghu Ram EV, Kumar A, Biswas S, Kumar A, Chaubey S, Siddiqi MI, et al. Nuclear gyrB encodes a functional subunit of the Plasmodium falciparum gyrase that is involved in apicoplast DNA replication. Mol Biochem Parasitol. 2007;154(1):30-9. https://doi.org/10.1016/j.molbiopara.2007.04.001
  27. Goodman CD, Su V, McFadden GI. The effects of anti-bacterials on the malaria parasite Plasmodium falciparum. Mol Biochem Parasitol. 2007;152(2):181-91. https://doi.org/10.1016/j.molbiopara.2007.01.005
  28. Singh D, Kumar A, Raghu Ram EV, Habib S. Multiple replication origins within the inverted repeat region of the Plasmodium falciparum apicoplast genome are differentially activated. Mol Biochem Parasitol. 2005;139(1):99-106. https://doi.org/10.1016/j.molbiopara.2004.09.011
  29. Onodera Y, Tanaka M, Sato K. Inhibitory activity of quinolones against DNA gyrase of Mycobacterium tuberculosis. J Antimicrob Chemother. 2001;47(4):447-50. https://doi.org/10.1093/jac/47.4.447
  30. Dahl EL, Rosenthal PJ. Multiple antibiotics exert delayed effects against the Plasmodium falciparum apicoplast. Antimicrob Agents Chemother. 2007;51(10):3485-90. https://doi.org/10.1128/AAC.00527-07
  31. Goodman CD, McFadden GI. Ycf93 (Orf105), a small apicoplast-encoded membrane protein in the relict plastid of the malaria parasite Plasmodium falciparum that is conserved in Apicomplexa. PLoS One. 2014;9(4):e91178. https://doi.org/10.1371/journal.pone.0091178
  32. Gray MW, Lang BF. Transcription in chloroplasts and mitochondria: a tale of two polymerases. Trends Microbiol. 1998;6(1):1-3. https://doi.org/10.1016/S0966-842X(97)01182-7
  33. Li J, Maga JA, Cermakian N, Cedergren R, Feagin JE. Identification and characterization of a Plasmodium falciparum RNA polymerase gene with similarity to mitochondrial RNA polymerases. Mol Biochem Parasitol. 2001;113(2):261-9. https://doi.org/10.1016/S0166-6851(01)00223-7
  34. McConkey GA, Rogers MJ, McCutchan TF. Inhibition of Plasmodium falciparum protein synthesis. targeting the plastid-like organelle with thiostrepton. J Biol Chem. 1997;272(4):2046-9. https://doi.org/10.1074/jbc.272.4.2046
  35. Dahl EL, Shock JL, Shenai BR, Gut J, DeRisi JL, Rosenthal PJ. Tetracyclines specifically target the apicoplast of the malaria parasite Plasmodium falciparum. Antimicrob Agents Chemother. 2006;50(9):3124-31. https://doi.org/10.1128/AAC.00394-06
  36. Pradel G, Schlitzer M. Antibiotics in malaria therapy and their effect on the parasite apicoplast. Curr Mol Med. 2010;10(3):335-349. https://doi.org/10.2174/156652410791065273
  37. Chaubey S, Kumar A, Singh D, Habib S. The apicoplast of Plasmodium falciparum is translationally active. Mol Microbiol. 2005;56(1):81-9. https://doi.org/10.1111/j.1365-2958.2005.04538.x
  38. Haider A, Allen SM, Jackson KE, Ralph SA, Habib S. Targeting and function of proteins mediating translation initiation in organelles of Plasmodium falciparum. Mol Microbiol. 2015;96(4):796-814. https://doi.org/10.1111/mmi.12972
  39. Gupta A, Mir SS, Jackson KE, Lim EE, Shah P, Sinha A, et al. Recycling factors for ribosome disassembly in the apicoplast and mitochondrion of Plasmodium falciparum. Mol Microbiol. 2013;88(5):891-905. https://doi.org/10.1111/mmi.12230
  40. Budimulja AS, Syafruddin, Tapchaisri P, Wilairat P, Marzuki S. The sensitivity of Plasmodium protein synthesis to prokaryotic ribosomal inhibitors. Mol Biochem Parasitol. 1997;84(1):137-41. https://doi.org/10.1016/S0166-6851(96)02781-8
  41. Lemgruber L, Kudryashev M, Dekiwadia C, Riglar DT, Baum J, Stahlberg H, et al. Cryo-electron tomography reveals four-membrane architecture of the Plasmodium apicoplast. Malar J. 2013;12:25. https://doi.org/10.1186/1475-2875-12-25
  42. Botte CY, Dubar F, McFadden GI, Marechal E, Biot C. Plasmodium falciparum apicoplast drugs: targets or off-targets?. Chem Rev. 2012;112(3):1269-83. https://doi.org/10.1021/cr200258w
  43. Lindner J, Meissner KA, Schettert I, Wrenger C. Trafficked proteins-druggable in Plasmodium falciparum?. Int J Cell Biol. 2013;2013:e435981.
  44. Sahu R, Walker LA, Tekwani BL. In vitro and in vivo anti-malarial activity of tigecycline, a glycylcycline antibiotic, in combination with chloroquine. Malar J. 2014;13:414. https://doi.org/10.1186/1475-2875-13-414
  45. Shears MJ, Botte CY, McFadden GI. Fatty acid metabolism in the Plasmodium apicoplast: Drugs, doubts and knockouts. Mol Biochem Parasitol. 2015;199(1-2):34-50. https://doi.org/10.1016/j.molbiopara.2015.03.004
  46. Waller RF, Keeling PJ, Donald RGK, Striepen B, Handman E, Lang-Unnasch N, et al. Nuclear-encoded proteins target to the plastid in Toxoplasma gondii and Plasmodium falciparum. Proc Natl Acad Sci USA. 1998;95(21):12352-7. https://doi.org/10.1073/pnas.95.21.12352
  47. McLeod R, Muench SP, Rafferty JB, Kyle DE, Mui EJ, Kirisits MJ, et al. Triclosan inhibits the growth of Plasmodium falciparum and Toxoplasma gondii by inhibition of apicomplexan Fab I. Int J Parasitol. 2001;31(2):109-13. https://doi.org/10.1016/S0020-7519(01)00111-4
  48. Haussig JM, Matuschewski K, Kooij TW. Inactivation of a Plasmodium apicoplast protein attenuates formation of liver merozoites. Mol Microbiol. 2011;81(6):1511-25. https://doi.org/10.1111/j.1365-2958.2011.07787.x
  49. Qidwai T, Priya A, Khan NA, Tripathi H, Khan F, Darokar MP, et al. Antimalarial drug targets and drugs targeting dolichol metabolic pathway of Plasmodium falciparum. Curr Drug Targets. 2014;15(4):374-409. https://doi.org/10.2174/13894501113149990169
  50. Lichtenthaler HK, Schwender J, Disch A, Rohmer M. Biosynthesis of isoprenoids in higher plant chloroplasts proceeds via a mevalonate-independent pathway. FEBS Letters. 1997;400(3):271-4. https://doi.org/10.1016/S0014-5793(96)01404-4
  51. Baumeister S, Wiesner J, Reichenberg A, Hintz M, Bietz S, Harb OS, et al. Fosmidomycin uptake into Plasmodium and Babesia-infected erythrocytes is facilitated by parasite-induced new permeability pathways. PLoS One. 2011;6(5):e19334. https://doi.org/10.1371/journal.pone.0019334
  52. Jomaa H, Wiesner J, Sanderbrand S, Altincicek B, Weidemeyer C, Hintz M, et al. Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs. Science. 1999;285(5433):1573-6. https://doi.org/10.1126/science.285.5433.1573
  53. Gisselberg JE, Dellibovi-Ragheb TA, Matthews KA, Bosch G, Prigge ST. The suf iron-sulfur cluster synthesis pathway is required for apicoplast maintenance in malaria parasites. PLoS Pathog. 2013;9(9):e1003655. https://doi.org/10.1371/journal.ppat.1003655
  54. Dellibovi-Ragheb TA, Gisselberg JE, Prigge ST. Parasites FeS up: iron-sulfur cluster biogenesis in eukaryotic pathogens. PLoS Pathog. 2013;9(4):e1003227. https://doi.org/10.1371/journal.ppat.1003227
  55. Seliverstov AV, Zverkov OA, Istomina SN, Pirogov SA, Kitsis PS. Comparative analysis of apicoplast-targeted protein extension lengths in apicomplexan parasites. Biomed Res Int. 2015;2015:e452958.
  56. Laleve A, Vallieres C, Golinelli-Cohen MP, Bouton C, Song Z, Pawlik G, et al. The antimalarial drug primaquine targets Fe-S cluster proteins and yeast respiratory growth. Redox Biol. 2016;7:21-9. https://doi.org/10.1016/j.redox.2015.10.008
  57. Wilson CM, Smith AB, Baylon RV. Characterization of the delta-aminolevulinate synthase gene homologue in P. falciparum. Mol Biochem Parasitol. 1996;75(2):271-6. https://doi.org/10.1016/0166-6851(95)02531-6
  58. Surolia N, Pasmanaban G. de novo biosynthesis of heme offers a new chemotherapeutic target in the human malarial parasite. Biochem Biophys Res Commun. 1992;187(2):744-50. https://doi.org/10.1016/0006-291X(92)91258-R
  59. Bonday ZQ, Dhanasekaran S, Rangarajan PN, Padmanaban G. Import of host delta-aminolevulinate dehydratase into the malarial parasite: identification of a new drug target. Nat Med. 2000;6(8):898-903. https://doi.org/10.1038/78659
  60. Ke H, Sigala PA, Miura K, Morrisey JM, Mather MW, Crowley JR, et al. The heme biosynthesis pathway is essential for Plasmodium falciparum development in mosquito stage but not in blood stages. J Biol Chem. 2014;289(50):34827-37. https://doi.org/10.1074/jbc.M114.615831
  61. Nagaraj VA, Sundaram B, Varadarajan NM, Subramani PA, Kalappa DM, Ghosh SK, et al. Malaria parasite-synthesized heme is essential in the mosquito and liver stages and complements host heme in the blood stages of infection. PLoS Pathog. 2013;9(8):e1003522. https://doi.org/10.1371/journal.ppat.1003522
  62. Yeh E, DeRisi JL. Chemical rescue of malaria parasites lacking an apicoplast defines organelle function in blood-stage Plasmodium falciparum. PLoS Biol. 2011;9(8):e1001138. https://doi.org/10.1371/journal.pbio.1001138
  63. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, et al. AutoDock4 and AutoDock-Tools4: automated docking with selective receptor flexibility. J Comput Chem. 2009;30(16):2785-91. https://doi.org/10.1002/jcc.21256
  64. Gupta A, Shah P, Haider A, Gupta K, Siddiqi MI, Ralph SA, et al. Reduced ribosomes of the apicoplast and mitochondrion of Plasmodium spp. and predicted interactions with antibiotics. Open Biol. 2014;4(5):e140045. https://doi.org/10.1098/rsob.140045
  65. Sawhney B, Chopra K, Misra R, Ranjan A. Identification of Plasmodium falciparum apicoplast-targeted tRNA-guanine transglycosylase and its potential inhibitors using comparative genomics, molecular modelling, docking and simulation studies. J Biomol Struct Dyn. 2015;33(11):2404-20. https://doi.org/10.1080/07391102.2015.1040074
  66. Cilingir G, Broschat SL, Lau AO. ApicoAP: the first computational model for identifying apicoplast-targeted proteins in multiple species of Apicomplexa. PLoS One. 2012;7(5):e36598. https://doi.org/10.1371/journal.pone.0036598
  67. Pham JS, Sakaguchi R, Yeoh LM, De Silva NS, McFadden GI, Hou YM, et al. A dual-targeted aminoacyl-tRNA synthetase in Plasmodium falciparum charges cytosolic and apicoplast tRNACys. Biochem J. 2014;458(3):513-23. https://doi.org/10.1042/BJ20131451
  68. Jackson KE, Pham JS, Kwek M, De Silva NS, Allen SM, Goodman CD, et al. Dual targeting of aminoacyl-tRNA synthetases to the apicoplast and cytosol in Plasmodium falciparum. Int J Parasitol. 2012;42(2):177-86. https://doi.org/10.1016/j.ijpara.2011.11.008
  69. McFadden GI, Roos DS. Apicomplexan plastids as drug targets. Trends Microbiol. 1999;7(8):328-33. https://doi.org/10.1016/S0966-842X(99)01547-4

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