Summary of Study ST001175
This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR000787. The data can be accessed directly via it's Project DOI: 10.21228/M8Z97B This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
Study ID | ST001175 |
Study Title | Multi-omics analysis demonstrates unique mode of action of a potent new antimalarial compound, JPC-3210, against Plasmodium falciparum |
Study Summary | 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. |
Institute | Monash University |
Last Name | Siddiqui |
First Name | Ghizal |
Address | 381 Royal Parade, Parkville |
ghizal.siddiqui@monash.edu | |
Phone | 99039282 |
Submit Date | 2019-04-25 |
Raw Data Available | Yes |
Raw Data File Type(s) | raw(Thermo) |
Analysis Type Detail | LC-MS |
Release Date | 2019-05-15 |
Release Version | 1 |
Select appropriate tab below to view additional metadata details:
Factors:
Subject type: Other; Subject species: Plasmodium falciparum (Factor headings shown in green)
mb_sample_id | local_sample_id | Condition |
---|---|---|
SA081519 | P_Aqm_1 | Aqm treated |
SA081520 | P_Aqm_3 | Aqm treated |
SA081521 | P_Aqm_2 | Aqm treated |
SA081522 | P_Aqm_4 | Aqm treated |
SA081523 | P_Atov_2 | Atov treated |
SA081524 | P_Atov_4 | Atov treated |
SA081525 | P_Atov_1 | Atov treated |
SA081526 | P_Atov_3 | Atov treated |
SA081527 | Blank_3 | Blank |
SA081528 | Blank_2 | Blank |
SA081529 | Blank_6 | Blank |
SA081530 | Blank_1 | Blank |
SA081531 | Blank_4 | Blank |
SA081532 | Blank_5 | Blank |
SA081533 | P_CQ_4 | CQ treated |
SA081534 | P_CQ_3 | CQ treated |
SA081535 | P_CQ_2 | CQ treated |
SA081536 | P_CQ_1 | CQ treated |
SA081537 | P_DHA_4 | DHA treated |
SA081538 | P_DHA_3 | DHA treated |
SA081539 | P_DHA_2 | DHA treated |
SA081540 | P_DHA_1 | DHA treated |
SA081541 | P_DMSO_6 | DMSO treated |
SA081542 | P_DMSO_8 | DMSO treated |
SA081543 | P_DMSO_7 | DMSO treated |
SA081544 | P_DMSO_2 | DMSO treated |
SA081545 | P_DMSO_3 | DMSO treated |
SA081546 | P_DMSO_4 | DMSO treated |
SA081547 | P_DMSO_5 | DMSO treated |
SA081548 | P_JPC_3 | JPC treated |
SA081549 | P_JPC_2 | JPC treated |
SA081550 | P_JPC_1 | JPC treated |
SA081551 | P_LF_1 | LF treated |
SA081552 | P_LF_2 | LF treated |
SA081553 | P_LF_4 | LF treated |
SA081554 | P_LF_3 | LF treated |
SA081555 | P_MQ_2 | MQ treated |
SA081556 | P_MQ_1 | MQ treated |
SA081557 | P_MQ_3 | MQ treated |
SA081558 | P_MQ_4 | MQ treated |
SA081559 | P_PYN_3 | PYN treated |
SA081560 | P_PYN_4 | PYN treated |
SA081561 | P_PYN_1 | PYN treated |
SA081562 | P_PYN_2 | PYN treated |
SA081563 | QC_P_6 | QC |
SA081564 | QC_P_5 | QC |
SA081565 | QC_P_3 | QC |
SA081566 | QC_P_1 | QC |
SA081567 | QC_P_2 | QC |
SA081568 | QC_P_4 | QC |
SA081569 | P_TQ_1 | TQ treated |
SA081570 | P_TQ_2 | TQ treated |
SA081571 | P_TQ_3 | TQ treated |
SA081572 | P_TQ_4 | TQ treated |
Showing results 1 to 54 of 54 |