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Mol Cell Proteomics. 2019 Dec 13. pii: mcp.RA119.001797. doi: 10.1074/mcp.RA119.001797. [Epub ahead of print]

Multi-omic characterisation of the mode of action of a potent new antimalarial compound, JPC-3210, against Plasmodium falciparum.

Author information

1
Australian Defence Force Malaria and Infectious Disease Institute, Brisbane, Australia, Australia.
2
Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia, Australia.
3
Monash University, Australia.
4
Jacobus Pharmaceutical Company, Plainsboro, NJ., United States.
5
ustralian Defence Force Malaria and Infectious Disease Institute, Brisbane, Australia, Australia.
6
Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia, Australia ghizal.siddiqui@monash.edu.

Abstract

The increasing incidence of antimalarial drug resistance to the first-line artemisinin combination therapies underpins an urgent need for new antimalarial drugs, ideally with a novel mode of action. The recently developed 2-aminomethylphenol, JPC-3210, (MMV 892646) is an erythrocytic schizonticide with potent in vitro antimalarial activity against multidrug-resistant Plasmodium falciparum lines, low cytotoxicity, potent in vivo efficacy against murine malaria, and favourable preclinical pharmacokinetics including a lengthy plasma elimination half-life. To investigate the impact of JPC-3210 on biochemical pathways within P. falciparum-infected red blood cells, we have applied a "multi-omics" workflow based on high resolution orbitrap mass spectrometry combined with biochemical approaches. Metabolomics, peptidomics and hemoglobin fractionation analyses revealed a perturbation in hemoglobin metabolism following JPC-3210 exposure. The metabolomics data demonstrated a specific depletion of short hemoglobin-derived peptides, peptidomics analysis revealed a depletion of longer hemoglobin-derived peptides, and the hemoglobin fractionation assay demonstrated decreases in hemoglobin, heme and hemozoin levels. In order to further elucidate the mechanism responsible for inhibition of hemoglobin metabolism, we used in vitro β-hematin polymerisation assays and showed JPC-3210 to be an intermediate inhibitor of β-hematin polymerisation, about 10-fold less potent then the quinoline antimalarials, such as chloroquine and mefloquine. Furthermore, quantitative proteomics analysis showed that JPC-3210 treatment results in a distinct proteomic signature in comparison to other known antimalarials. Whilst JPC-3210 clustered closely with mefloquine in the metabolomics and proteomics analyses, a key differentiating signature for JPC-3210 was the significant enrichment of parasite proteins involved in regulation of translation. These studies revealed that the mode of action for JPC-3210 involves inhibition of the hemoglobin digestion pathway and elevation of regulators of protein translation. Importantly, JPC-3210 demonstrated rapid parasite killing kinetics compared to other quinolones, suggesting that JPC-3210 warrants further investigation as a potentially long acting partner drug for malaria treatment.

KEYWORDS:

2-aminomethylphenol; Drug targets*; Malaria; Metabolites; Metabolomics; Peptidomics; Proteomics; antimalarial drug discovery; mode of action

PMID:
31836637
DOI:
10.1074/mcp.RA119.001797
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