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.
Highlights
Over the last decades, antimalarial drug resistance in Plasmodium falciparum has presented an obstacle for the malaria elimination program of the World Health Organization (WHO) [1]
ICL-M has the ability to kill both the ring and trophozoite stages of P. falciparum, but the trophozoite stage is slightly less sensitive to treatment with ICL-M compared with the early stage
We studied the effects of ICL-M on P. falciparum by assessing its stage-specific activity, topoisomerase II (topo II) activity inhibition, and time-dependent effect as well as by performing a proteomic analysis and a Transmission electron microscopy (TEM) morphology analysis
Summary
Antimalarial drug resistance in Plasmodium falciparum has presented an obstacle for the malaria elimination program of the World Health Organization (WHO) [1]. Isocryptolepine was first isolated from the roots of C. sanguinolenta in 1995, and its structure was determined to be 5-methyl-5H-indolo[3,2-c]quinoline. The results demonstrated that isocryptolepine possesses activity against both drug-sensitive and drug-resistance strains of P. falciparum [3,4,5]. In 2015, an isocryptolepine derivative containing fluorine and bromine, 8-bromo-2-fluoro-5-methyl-5H-indolo[3,2-c]quinoline (ICL-M), was reported to display an improved antimalarial activity against both drug-sensitive and drug-resistant strains and to induce less toxicity in human cells compared with the original isocryptolepine. ICL-M has indoloquinoline as its core structure, it could kill quinoline-resistant P. falciparum such as chloroquine-resistant and mefloquine-resistant strains [5]. Isocryptolepine derivatives have been reported to target human topoisomerase II (topo II) in several different types of cancer cells [8]. The targets and modes of action of ICL-M in malaria parasites remain unclear
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