Summary of Study ST002792

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 PR001740. The data can be accessed directly via it's Project DOI: 10.21228/M8SQ7X This work is supported by NIH grant, U2C- DK119886.

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This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

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Study IDST002792
Study TitleChemoproteomics validates selective targeting of Plasmodium M1 alanyl aminopeptidase as a cross-species strategy to treat malaria
Study SummaryAll current treatments for malaria are threatened by drug resistance, and new drug candidates that act on novel pathways are urgently needed. Here, we describe MIPS2673, a selective inhibitor of the Plasmodium M1 alanyl metalloaminopeptidase, which displays excellent in vitro antimalarial activity with no significant host cell toxicity. Biochemical assays revealed potent inhibition of recombinant Plasmodium falciparum (PfA-M1) and Plasmodium vivax (Pv-M1) M1 metalloaminopeptidases, with selectivity over other Plasmodium and human aminopeptidases. Orthogonal chemoproteomic methods based on thermal stability and limited proteolysis reproducibly identified PfA-M1 as the sole target of MIPS2673 in parasites from approximately 2,000 detected proteins. Furthermore, the limited proteolysis approach enabled estimation of the binding site on PfA-M1 to within ~5 Å of that determined by X-ray crystallography. Functional investigation by untargeted metabolomics further demonstrated that MIPS2673 inhibits the key role of PfA-M1 in haemoglobin digestion. Combined, our proteomics and metabolomics target deconvolution strategies provided unbiased confirmation of the on-target activity of a PfA-M1 inhibitor, and validated selective inhibition of this enzyme as a promising multi-stage and cross-species antimalarial strategy.
Institute
Monash University
Last NameSiddiqui
First NameGhizal
Address381 Royal Parade, Parkville, Melbourne, Victoria, 3052, Australia
Emailghizal.siddiqui@monash.edu
Phone99039282
Submit Date2023-07-23
Raw Data AvailableYes
Raw Data File Type(s)raw(Thermo)
Analysis Type DetailLC-MS
Release Date2023-08-10
Release Version1
Ghizal Siddiqui Ghizal Siddiqui
https://dx.doi.org/10.21228/M8SQ7X
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

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Combined analysis:

Analysis ID AN004542 AN004543
Analysis type MS MS
Chromatography type HILIC HILIC
Chromatography system Thermo Dionex Ultimate 3000 RS Thermo Dionex Ultimate 3000 RS
Column ZIC-pHILIC (150 x 4.6mm,5um) equipped with a guard (SeQuant,Merck) ZIC-pHILIC (150 x 4.6mm,5um) equipped with a guard (SeQuant,Merck)
MS Type ESI ESI
MS instrument type Orbitrap Orbitrap
MS instrument name Thermo Q Exactive Orbitrap Thermo Q Exactive Orbitrap
Ion Mode POSITIVE NEGATIVE
Units peak height peak height

Chromatography:

Chromatography ID:CH003412
Instrument Name:Thermo Dionex Ultimate 3000 RS
Column Name:ZIC-pHILIC (150 x 4.6mm,5um) equipped with a guard (SeQuant,Merck)
Column Temperature:25
Flow Gradient:0% B to 50% B over 15 min, then to 5% B at 18 min until 21 min, increasing to 80% B at 24 min until 32 min.
Flow Rate:0.3 ml/min
Solvent A:100% water; 20 mM ammonium carbonate
Solvent B:100% acetonitrile
Chromatography Type:HILIC
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