Birrell, Geoffrey W; Challis, Matthew P; De Paoli, Amanda; Anderson, Dovile; Devine, Shane M; Heffernan, Gavin D; Jacobus, David P; Edstein, Michael D; Siddiqui, Ghizal; Creek, Darren J
Multi-omic Characterization of the Mode of Action of a Potent New Antimalarial Compound, JPC-3210, Against Plasmodium falciparum
Teil von
  • Molecular & cellular proteomics, 2020-02, Vol.19 (2), p.308-325
Ort / Verlag
ROCKVILLE: Elsevier Inc
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HighWire Press (Free Journals)
The mode of action of novel antimalarial, JPC-3210 has been revealed using biochemical assays combined with several multi-omics techniques, including proteomics, peptidomics and metabolomics. Metabolomics and peptidomics, in combination with hemoglobin fractionation assays and β-hematin polymerization assays, revealed JPC-3210 to inhibit the parasite's hemoglobin digestion pathway. Proteomics analysis of JPC-3210-treated parasites identified significant enrichment for proteins involved in the regulation of translation. [Display omitted] Highlights •Multi-omics analysis on mode of action of novel antimalarial, JPC-3210•JPC-3210 has rapid parasite killing kinetics.•Metabolomics and peptidomics demonstrated JPC-3210 inhibits hemoglobin digestion.•Proteomics demonstrated JPC-3210 enriches for translation regulation proteins. 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 favorable 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. To further elucidate the mechanism responsible for inhibition of hemoglobin metabolism, we used in vitro β-hematin polymerization assays and showed JPC-3210 to be an intermediate inhibitor of β-hematin polymerization, about 10-fold less potent then the quinoline antimalarials, such as chloroquine and mefloquine. Further, quantitative proteomics analysis showed that JPC-3210 treatment results in a distinct proteomic signature compared with other known antimalarials. While 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 with other quinolones, suggesting that JPC-3210 warrants further investigation as a potentially long acting partner drug for malaria treatment.

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