Proteomic analysis of Plasmodium falciparum response to isocryptolepine derivative.

Abstract

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.

• Authors: Kitiya Rujimongkon, Mathirut Mungthin, Jumreang Tummatorn, Sumate Ampawong, Poom Adisakwattana, Usa Boonyuen, Onrapak Reamtong
• Journal: PloS one (PLoS One) Vol. 14 Issue 8 Pg. e0220871 ( 2019) ISSN: 1932-6203 [Electronic] United States
• PMID: 31393938 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimalarials
• Indole Alkaloids
• Protozoan Proteins
• Quinolines
• isocryptolepine
• DNA Topoisomerases, Type II

Topics

• Antimalarials
• DNA Topoisomerases, Type II (drug effects)
• Gene Expression Regulation (drug effects)
• Humans
• Indole Alkaloids (chemistry, pharmacology)
• Malaria (drug therapy, parasitology)
• Metabolic Networks and Pathways (drug effects)
• Plasmodium falciparum (drug effects)
• Proteomics (methods)
• Protozoan Proteins (drug effects)
• Quinolines (chemistry, pharmacology)
• Ribosomes (drug effects)