Plasmodium falciparum endoplasmic reticulum-resident calcium binding protein is a possible target of synthetic antimalarial endoperoxides, n-89 and N-251

Masayuki Morita, Hitomi Sanai, Akiko Hiramoto, Akira Sato, Osamu Hiraoka, Takaya Sakura, Osamu Kaneko, Araki Masuyama, Masatomo Nojima, Yusuke Wataya, Hye-Sook Kim

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

The endoperoxide artemisinin is a current first-line antimalarial and a critical component of the artemisinin-based combination therapies (ACT) recommended by WHO for treatment of Plasmodium falciparum, the deadliest of malaria parasites. However, recent emergence of the artemisinin-resistant P. falciparum urged us to develop new antimalarial drugs. We have shown that synthetic endoperoxides N-89 and its hydroxyl derivative N-251 had high antimalarial activities both in vivo and in vitro. However, the mechanisms including the cellular targets of the endoperoxide antimalarials are not well understood. Thus, in this study, we employed chemical proteomics to survey potential molecular targets of endoperoxides by evaluating P. falciparum proteins capable to associate with endoperoxide structure (N-346, a carboxyamino derivative of N-89). We also analyzed the protein expression profiles of malaria parasites treated with N-89 or N-251 to explore possible changes associated with the drug action. From these experiments, we found that P. falciparum endoplasmic reticulum-resident calcium binding protein (PfERC) had high affinity to the endoperoxide structure (N-346) and was decreased by treatment with N-89 or N-251. PfERC is a member of CREC protein family, a potential disease marker and also a potential target for therapeutic intervention. We propose that the PfERC is a strong candidate of the endoperoxide antimalarial's target.

Original languageEnglish
Pages (from-to)5704-5711
Number of pages8
JournalJournal of Proteome Research
Volume11
Issue number12
DOIs
Publication statusPublished - Dec 7 2012

Fingerprint

Calcium-Binding Proteins
Antimalarials
Plasmodium falciparum
Endoplasmic Reticulum
Parasites
Derivatives
Proteins
Falciparum Malaria
Hydroxyl Radical
Proteomics
Malaria
Therapeutics
Pharmaceutical Preparations
artemisinine
Experiments

Keywords

  • antimalarial mechanism
  • chemical proteomics
  • endoperoxides
  • malaria
  • Plasmodium falciparum
  • Plasmodium falciparum endoplasmic reticulum-resident calcium binding protein (Pf ERC)

ASJC Scopus subject areas

  • Biochemistry
  • Chemistry(all)

Cite this

Plasmodium falciparum endoplasmic reticulum-resident calcium binding protein is a possible target of synthetic antimalarial endoperoxides, n-89 and N-251. / Morita, Masayuki; Sanai, Hitomi; Hiramoto, Akiko; Sato, Akira; Hiraoka, Osamu; Sakura, Takaya; Kaneko, Osamu; Masuyama, Araki; Nojima, Masatomo; Wataya, Yusuke; Kim, Hye-Sook.

In: Journal of Proteome Research, Vol. 11, No. 12, 07.12.2012, p. 5704-5711.

Research output: Contribution to journalArticle

Morita, M, Sanai, H, Hiramoto, A, Sato, A, Hiraoka, O, Sakura, T, Kaneko, O, Masuyama, A, Nojima, M, Wataya, Y & Kim, H-S 2012, 'Plasmodium falciparum endoplasmic reticulum-resident calcium binding protein is a possible target of synthetic antimalarial endoperoxides, n-89 and N-251', Journal of Proteome Research, vol. 11, no. 12, pp. 5704-5711. https://doi.org/10.1021/pr3005315
Morita, Masayuki ; Sanai, Hitomi ; Hiramoto, Akiko ; Sato, Akira ; Hiraoka, Osamu ; Sakura, Takaya ; Kaneko, Osamu ; Masuyama, Araki ; Nojima, Masatomo ; Wataya, Yusuke ; Kim, Hye-Sook. / Plasmodium falciparum endoplasmic reticulum-resident calcium binding protein is a possible target of synthetic antimalarial endoperoxides, n-89 and N-251. In: Journal of Proteome Research. 2012 ; Vol. 11, No. 12. pp. 5704-5711.
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AU - Wataya, Yusuke

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