PXD013539-1

PXD013539 is an original dataset announced via ProteomeXchange.

Title	Multi-omics analysis demonstrates unique mode of action of a potent new antimalarial compound, JPC-3210, against Plasmodium falciparum
Description	The increasing incidence of antimalarial drug resistance to the first-line artemisinins, and their combination partner drugs, underpins an urgent need for new antimalarial drugs, ideally with a novel mechanism 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, low cytotoxicity, potent in vivo efficacy against murine malaria, and favourable preclinical pharmacokinetics, including a lengthy plasma elimination half-life. This study demonstrates the application of a “multi-omics” workflow based on high resolution orbitrap mass spectrometry to investigate the impact of JPC-3210 on biochemical pathways within P. falciparum infected red blood cells. Metabolomics and peptidomics analysis revealed a perturbation in hemoglobin metabolism following JPC-3210 exposure. The metabolomics data demonstrated a depletion in short hemoglobin-derived peptides, while peptidomics analysis showed a depletion in longer hemoglobin-derived peptides. 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. 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. In conclusion, multi-omics studies using high resolution mass spectrometry revealed JPC-3210 to possess a unique mechanism of action involving inhibition of hemoglobin digestion, depletion of DNA replication and synthesis proteins, and elevation of regulators of protein translation. Importantly, this mechanism is distinct from currently-used antimalarials, suggesting that JPC-3210 warrants further investigation as a potentially useful new antimalarial agent.
HostingRepository	PRIDE
AnnounceDate	2019-12-20
AnnouncementXML	Submission_2019-12-20_04:18:44.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Ghizal Siddiqui
SpeciesList	scientific name: Plasmodium falciparum 3D7; NCBI TaxID: 36329; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2019-04-17 04:00:25	ID requested
⏵ 1	2019-12-20 04:18:45	announced
2	2024-10-22 04:54:53	announced	2024-10-22: Updated project metadata.

Birrell GW, Challis MP, De Paoli A, Anderson D, Devine SM, Heffernan GD, Jacobus DP, Edstein MD, Siddiqui G, Creek DJ, . Mol Cell Proteomics, 19(2):308-325(2020) [pubmed]

submitter keyword: 2-aminomethylphenol, mechanism of action, antimalarial drug discovery, metabolomics, proteomics

Darren Creek
contact affiliation	Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia
contact email	darren.creek@monash.edu
lab head
Ghizal Siddiqui
contact affiliation	Monash University
contact email	ghizal.siddiqui@monash.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD013539
     1. Label: PRIDE project
     2. Name: Multi-omics analysis demonstrates unique mode of action of a potent new antimalarial compound, JPC-3210, against Plasmodium falciparum