Parasites, Hosts and Diseases

The Korea Society for Parasitology and Tropical Medicine (대한기생충학·열대의학회)
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Antimalarial effect of synthetic endoperoxide on synchronized Plasmodium chabaudi infected mice

  • Nagwa S. M. Aly (Division of International Infectious Diseases Control, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University) ;
  • Hiroaki Matsumori (Division of International Infectious Diseases Control, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University) ;
  • Thi Quyen Dinh (Division of International Infectious Diseases Control, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University) ;
  • Akira Sato (Division of International Infectious Diseases Control, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University) ;
  • Shin-Ichi Miyoshi (Department of Sanitary Microbiology, Faculty of Pharmaceutical Sciences, Okayama University) ;
  • Kyung-Soo Chang (Department of Clinical Laboratory Science, College of Health Sciences, Catholic University of Pusan) ;
  • Hak Sun Yu (Department of Parasitology and Tropical Medicine, School of Medicine, Pusan National University) ;
  • Fumie Kobayashi (Department of Environmental Science, School of Life Environmental Science, Azabu University) ;
  • Hye-Sook Kim (Division of International Infectious Diseases Control, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University)
  • Received : 2022.09.10
  • Accepted : 2022.12.12
  • Published : 2023.02.28
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Abstract

The discovery of new antimalarial drugs can be developed using asynchronized Plasmodium berghei malaria parasites in vivo in mice. Studies on a particular stage are also required to assess the effectiveness and mode of action of drugs. In this report, we used endoperoxide 6-(1,2,6,7-tetraoxaspiro [7.11] nonadec-4-yl) hexan-1-ol (N-251) as a model antimalarial compound on P. chabaudi parasites. We examined the antimalarial effect of N-251 against ring-stage- and trophozoite-stage-rich P. chabaudi parasites and asynchronized P. berghei parasites using the 4-day suppressive test. The ED50 values were 27, 22, and 22 mg/kg, respectively, and the antimalarial activity of N-251 was verified in both rodent malaria parasites. To assess the stage-specific effect of N-251 in vivo, we evaluated the change of parasitemia and distribution of parasite stages using ring-stage- and trophozoite-stage-rich P. chabaudi parasites with one-day drug administration for one life cycle. We discovered that the parasitemias decreased after 13 and 9 hours post-treatment in the ring-stage- and trophozoite-stage-rich groups, respectively. Additionally, in the ring-stage-rich N-251 treated group, the ring-stage parasites hindered trophozoite parasite development. For the trophozoite-stage-rich N-251 treated group, the distribution of the trophozoite stage was maintained without a change in parasitemia until 9 hours. Because of these findings, it can be concluded that N-251 suppressed the trophozoite stage but not the ring stage. We report for the first time that N-251 specifically suppresses the trophozoite stage using P. chabaudi in mice. The results show that P. chabaudi is a reliable model for the characterization of stage-specific antimalarial effects.

Keywords

Acknowledgement

This study was partially supported by a grant from the Program of the Japan Initiative for Global Research Network on Infectious Diseases (J-GRID, JP22wm0125004) from the Ministry of Education, Culture, Sports, Science, and Technology in Japan (MEXT), and the Japan Agency for Medical Research and Development (AMED). We thank Taiki Osato (Okayama University) for the partial experiments and discussion.

References

  1. Hodel EM, Kay K, Hastings IM. 2016. Incorporating stage-specific drug action into pharmacological modeling of antimalarial drug treatment. Antimicrob Agents Chemother 2016;60(5):2747-2756. https://doi.org/10.1128/AAC.01172-15
  2. Moreno A, Badell E, Van Rooijen N, Druilhe P. Human malaria in immunocompromised mice: new in vivo model for chemotherapy studies. Antimicrob Agents Chemother 2001;45(6):1847-1853. https://doi.org/10.1128/AAC.45.6.1847-1853.2001
  3. Fidock DA, Rosenthal PJ, Croft SL, Brun R, Nwaka S. Antimalarial drug discovery: efficacy models for compound screening. Nat Rev Drug Discov 2004;3(6):509-520. https://doi.org/10.1038 /nrd1416 https://doi.org/10.1038/nrd1416
  4. Wengelnik K, Vidal V, Ancelin ML, Cathiard AM, Morgat JL, et al. A class of potent antimalarials and their specific accumulation in infected erythrocytes. Science 2002;295(5558):1311-1314. https://doi.org/10.1126/science.1067236
  5. Owolabi ATY, Reece SE, Schneider P. Daily rhythms of both host and parasite affect antimalarial drug efficacy. Evol Med Public Health 2021;9(1):208-219. https://doi.org/10.1093/emph/eoab013
  6. Wilson DW, Langer C, Goodman CD, McFadden GI, Beeson JG. Defining the timing of action of antimalarial drugs against Plasmodium falciparum. Antimicrob Agents Chemother 2013;57(3):1455-1467. https://doi.org/10.1128/AAC.01881-12
  7. Kim HS, Nagai Y, Ono K, Begum K, Wataya Y, et al. Synthesis and antimalarial activity of novel medium-sized 1,2,4,5-tetraoxacycloalkanes. J Med Chem 2001;44(14):2357-2361. https://doi.org/10.1021/jm 010026g
  8. Sato A, Hiramoto A, Morita M, Matsumoto M, Komich Y, et al. Antimalarial activity of endoperoxide compound 6-(1,2,6,7-tetraoxaspiro [7.11] nonadec-4-yl) hexan-1-ol. Parasitol Int 2011;60(3):270-273. https://doi.org/10.1016/j.parint.2011.04.001
  9. Morita M, Koyama T, Sanai H, Sato A, Hiramoto A. Stage specific activity of synthetic antimalarial endoperoxides, N-89 and N-251, against Plasmodium falciparum. Parasitol Int 2015;64(1):113-117. https://doi.org/10.1016/j.parint.2014.10.007
  10. Leelaviwat N, Mekraksakit P, Cross KM, Landis DM, McLain M, et al. Melatonin: Translation of ongoing studies into possible therapeutic applications outside sleep disorders. Clin Ther 2022;44(5):783-812. https://doi.org/10.1016/j.clinthera.2022.03.008
  11. Hotta CT, Gazarini ML, Beraldo FH, Varotti FP, Lopes C, et al. Calcium-dependent modulation by melatonin of the circadian rhythm in malarial parasites. Nature Cell Biol 2000;2(7):466-468. https://doi.org/10.1038/35017112
  12. Mallaupoma LRC, Dias BKM, Singh MK, Honorio RI, Nakabashi M, et al. Decoding the role of melatonin structure on Plasmodium falciparum human malaria parasites synchronization using 2-sulfenylindoles derivatives. Biomolecules 2022;12(5):638. https://doi.org/10.3390/biom 12050638
  13. Peters W. The chemotherapy of rodent malaria, XXII. The value of drug-resistant strains of P. berghei in screening for blood schizontocidal activity. Ann Trop Med Parasitol 1975;69(2):155-171. https://doi.org/10.1080/00034983.1975.11686997
  14. Smith LM, Motta FC, Chopra G, Moch JK, Nerem RR, et al. An intrinsic oscillator drives the blood stage cycle of the malaria parasite Plasmodium falciparum. Science 2020;368(6492):754-759. https://doi.org/10.1126/science.aba4357
  15. Beraldo FH, Almeida FM, da Silva AM, Garcia CR. Cyclic AMP and calcium interplay as second messengers in melatonin-dependent regulation of Plasmodium falciparum cell cycle. J Cell Biol 2005;170(4):551-557. https://doi.org/10.1083/jcb.200505117
  16. Singh MK, Dias BKM, Garcia CRS. Role of melatonin in the synchronization of asexual forms in the parasite Plasmodium falciparum. Biomolecules 2020;10(9):1243. https://doi.org/10.3390/biom10091243
  17. Gibbs FP, Vriend J. The half-life of melatonin elimination from rat plasma. Endocrinology 1981;109(5):1796-1798. https://doi.org/10.1210/endo-109-5-1796
  18. Andersen LP, Gogenur I, Rosenberg J, Reiter RJ. The safety of melatonin in humans. Clin Drug Investig 2016;36(3):169-175. https://doi.org/10.1007/s40261-015-0368-5
  19. Pereira PHS, Garcia CRS. Melatonin action in Plasmodium infection: Searching for molecules that modulate the asexual cycle as a strategy to impair the parasite cycle. J Pineal Res 2021;70(1):e12700. https://doi.org/10.1111/jpi.12700
  20. Bagnaresi P, Alves E, Borges da Silva H, Epiphanio S, et al. Unlike the synchronous Plasmodium falciparum and P. chabaudi infection, the P. berghei and P. yoelii asynchronous infections are not affected by melatonin. Int J Gen Med 2009;2:47-55. https://doi.org/10.2147/ijgm.s3699
  21. Shuto S, Minakawa N, Niizuma S, Kim HS, Wataya Y, et al. New neplanocin analogs 12. An alternative synthesis of (6'R)-6'-C- methylneplanocin A (RMNPA), a novel potent anti-malarial agent. J Med Chem 2002;45(3):748-751. https://doi.org/10.1021/jm010374i
  22. Kim HS, Shibata Y, Wataya Y, Tsuchiya K, Masuyama A, et al. Synthesis and antimalarial activity of cyclic peroxides, 1,2,4,5,7-pentoxocanes and 1,2,4,5-tetroxanes. J Med Chem 1999;42(14):2604-2609. https://doi.org/10.1021/jm990014j
  23. Tsuchiya K, Hamada Y, Masuyama A, Nojima M, McCullough KJ, et al. Synthesis, crystal structure and anti-malarial activity of novel spiro-1,2,4,5-tetraoxacycloalkanes. Tetrahedron Lett 1999;40(21):4077-4080. https://doi.org/10.1016/S0040-4039(99)00653-X
  24. Miyaoka H, Shimomura M, Kimura H, Yamada Y, Kim HS, et al. Antimalarial activity of kalihinol A and new relative diterpenoids from the okinawan sponge, Acanthella sp. Tetrahedron 1998;54(44):13467-13474. https://doi.org/10.1016/S0040-4020(98)00818-7
  25. Aly NS, Hiramoto A, Sanai H, Hiraoka O, Hiramoto K, et al. Proteome analysis of new antimalarial endoperoxide against Plasmodium falciparum. Parasitol Res 2007;100(5):1119-1124. https://doi.org/10.1007/s00436-007-0460-8
  26. Morita M, Sanai H, Hiramoto A, Sato A, Hiraoka O, et al. Plasmodium falciparum endoplasmic reticulum-resident calcium binding protein is a possible target of synthetic antimalarial endoperoxides, N-89 and N-251. J Proteome Res 2012;11(12): 5704-5711. https://doi.org/10.1021/pr3005315