Proteomic analysis of Plasmodium falciparum response to isocryptolepine derivative.
Drug-resistant strains of malaria parasites have emerged for most of antimalarial medications. A new chemotherapeutic compound is needed for malarial therapy. Antimalarial activity against both drug-sensitive and drug-resistant P. falciparum has been reported for an isocryptolepine derivative, 8-bro...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2019-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0220871 |
| _version_ | 1818403730377146368 |
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| author | Kitiya Rujimongkon Mathirut Mungthin Jumreang Tummatorn Sumate Ampawong Poom Adisakwattana Usa Boonyuen Onrapak Reamtong |
| author_facet | Kitiya Rujimongkon Mathirut Mungthin Jumreang Tummatorn Sumate Ampawong Poom Adisakwattana Usa Boonyuen Onrapak Reamtong |
| author_sort | Kitiya Rujimongkon |
| collection | DOAJ |
| description | Drug-resistant strains of malaria parasites have emerged for most of antimalarial medications. A new chemotherapeutic compound is needed for malarial therapy. Antimalarial activity against both drug-sensitive and drug-resistant P. falciparum has been reported for an isocryptolepine derivative, 8-bromo-2-fluoro-5-methyl-5H-indolo[3,2-c]quinoline (ICL-M), which also showed less toxicity to human cells. ICL-M has indoloquinoline as a core structure and its mode of action remains unclear. Here, we explored the mechanisms of ICL-M in P. falciparum by assessing the stage-specific activity, time-dependent effect, a proteomic analysis and morphology. Since human topo II activity inhibition has been reported as a function of isocryptolepine derivatives, malarial topo II activity inhibition of ICL-M was also examined in this study. The ICL-M exhibited antimalarial activity against both the ring and trophozoite stages of P. falciparum. Our proteomics analysis revealed that a total of 112 P. falciparum proteins were differentially expressed after ICL-M exposure; among these, 58 and 54 proteins were upregulated and downregulated, respectively. Proteins localized in the food vacuole, nucleus, and cytoplasm showed quantitative alterations after ICL-M treatment. A bioinformatic analysis revealed that pathways associated with ribosomes, proteasomes, metabolic pathways, amino acid biosynthesis, oxidative phosphorylation, and carbon metabolism were significantly different in P. falciparum treated with ICL-M. Moreover, a loss of ribosomes was clearly observed by transmission electron microscopy in the ICL-M-treated P. falciparum. This finding is in agreement with the proteomics data, which revealed downregulated levels of ribosomal proteins following ICL-M treatment. Our results provide important information about the mechanisms by which ICL-M affects the malaria parasite, which may facilitate the drug development of isocryptolepine derivatives. |
| first_indexed | 2024-12-14T08:28:54Z |
| format | Article |
| id | doaj.art-6cdd728c4750480cad4d058940abbdd3 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-14T08:28:54Z |
| publishDate | 2019-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-6cdd728c4750480cad4d058940abbdd32022-12-21T23:09:34ZengPublic Library of Science (PLoS)PLoS ONE1932-62032019-01-01148e022087110.1371/journal.pone.0220871Proteomic analysis of Plasmodium falciparum response to isocryptolepine derivative.Kitiya RujimongkonMathirut MungthinJumreang TummatornSumate AmpawongPoom AdisakwattanaUsa BoonyuenOnrapak ReamtongDrug-resistant strains of malaria parasites have emerged for most of antimalarial medications. A new chemotherapeutic compound is needed for malarial therapy. Antimalarial activity against both drug-sensitive and drug-resistant P. falciparum has been reported for an isocryptolepine derivative, 8-bromo-2-fluoro-5-methyl-5H-indolo[3,2-c]quinoline (ICL-M), which also showed less toxicity to human cells. ICL-M has indoloquinoline as a core structure and its mode of action remains unclear. Here, we explored the mechanisms of ICL-M in P. falciparum by assessing the stage-specific activity, time-dependent effect, a proteomic analysis and morphology. Since human topo II activity inhibition has been reported as a function of isocryptolepine derivatives, malarial topo II activity inhibition of ICL-M was also examined in this study. The ICL-M exhibited antimalarial activity against both the ring and trophozoite stages of P. falciparum. Our proteomics analysis revealed that a total of 112 P. falciparum proteins were differentially expressed after ICL-M exposure; among these, 58 and 54 proteins were upregulated and downregulated, respectively. Proteins localized in the food vacuole, nucleus, and cytoplasm showed quantitative alterations after ICL-M treatment. A bioinformatic analysis revealed that pathways associated with ribosomes, proteasomes, metabolic pathways, amino acid biosynthesis, oxidative phosphorylation, and carbon metabolism were significantly different in P. falciparum treated with ICL-M. Moreover, a loss of ribosomes was clearly observed by transmission electron microscopy in the ICL-M-treated P. falciparum. This finding is in agreement with the proteomics data, which revealed downregulated levels of ribosomal proteins following ICL-M treatment. Our results provide important information about the mechanisms by which ICL-M affects the malaria parasite, which may facilitate the drug development of isocryptolepine derivatives.https://doi.org/10.1371/journal.pone.0220871 |
| spellingShingle | Kitiya Rujimongkon Mathirut Mungthin Jumreang Tummatorn Sumate Ampawong Poom Adisakwattana Usa Boonyuen Onrapak Reamtong Proteomic analysis of Plasmodium falciparum response to isocryptolepine derivative. PLoS ONE |
| title | Proteomic analysis of Plasmodium falciparum response to isocryptolepine derivative. |
| title_full | Proteomic analysis of Plasmodium falciparum response to isocryptolepine derivative. |
| title_fullStr | Proteomic analysis of Plasmodium falciparum response to isocryptolepine derivative. |
| title_full_unstemmed | Proteomic analysis of Plasmodium falciparum response to isocryptolepine derivative. |
| title_short | Proteomic analysis of Plasmodium falciparum response to isocryptolepine derivative. |
| title_sort | proteomic analysis of plasmodium falciparum response to isocryptolepine derivative |
| url | https://doi.org/10.1371/journal.pone.0220871 |
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