Summary of Study ST003144

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 PR001955. The data can be accessed directly via it's Project DOI: 10.21228/M8172C This work is supported by NIH grant, U2C- DK119886.

See: https://www.metabolomicsworkbench.org/about/howtocite.php

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.

Study ID	ST003144
Study Title	On-target, dual aminopeptidase inhibition provides cross-species antimalarial activity
Study Summary	To combat the global burden of malaria, development of new drugs to replace or complement current therapies are urgently required. Here we show that the compound MMV1557817 is a selective, nanomolar inhibitor of both Plasmodium falciparum and Plasmodium vivax aminopeptidases M1 and M17, leading to inhibition of end stage haemoglobin digestion in asexual parasites. MMV1557817 can kill sexual stage P. falciparum, is active against murine malaria and did not show any shift in activity against a panel of parasites resistant to other antimalarials. MMV1557817-resistant P. falciparum exhibited a slow growth rate that was quickly outcompeted by wild type parasites and were sensitised to the current clinical drug, artemisinin. Overall, these results confirm MMV1557817 as a lead compound for further drug development and highlight the potential of dual inhibition of M1 and M17 as an effective multi-species drug targeting strategy.
Institute	Monash University
Last Name	Siddiqui
First Name	Ghizal
Address	381 Royal Parade, Parkville, Melbourne, Victoria, 3052, Australia
Email	ghizal.siddiqui@monash.edu
Phone	99039282
Submit Date	2024-03-25
Raw Data Available	Yes
Raw Data File Type(s)	raw(Thermo)
Analysis Type Detail	LC-MS
Release Date	2024-04-18
Release Version	1

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Sample Preparation:

Sampleprep ID:	SP003268
Sampleprep Summary:	Metabolomics analysis of MMV1557817, MIPS2673 (ST002792) and 3 compared to DMSO control (ST002108): P. falciparum (3D7) cultures at 6% parasitaemia and 2% haematocrit were subject to double sorbitol synchronisation 14 hours apart, followed by further incubation for 28-42 h to achieve the desired trophozoite stage (28 hours post infection). Infected RBCs (2x108) were treated with 10x the EC50 of MMV1557817 (320 nM), MIPS2673 (1 µM), 3 (4.53 µM) for 1 h, after which metabolites were extracted, analysed and processed as previously described (7). Principal-component analysis (PCA) and hierarchical clustering algorithms were run also in Metaboanalyst (50). Metabolomics data are presented as relative abundance values from 4-7 biological replicates. Differences were determined using Welch’s t-test where significant interactions were observed. Significance was determined at p values < 0.05. The metabolomics data for 3, MIPS-2673 and drug-free controls were reported previously (7, 51).

Sampleprep ID:

SP003268

Sampleprep Summary:

Metabolomics analysis of MMV1557817, MIPS2673 (ST002792) and 3 compared to DMSO control (ST002108): P. falciparum (3D7) cultures at 6% parasitaemia and 2% haematocrit were subject to double sorbitol synchronisation 14 hours apart, followed by further incubation for 28-42 h to achieve the desired trophozoite stage (28 hours post infection). Infected RBCs (2x108) were treated with 10x the EC50 of MMV1557817 (320 nM), MIPS2673 (1 µM), 3 (4.53 µM) for 1 h, after which metabolites were extracted, analysed and processed as previously described (7). Principal-component analysis (PCA) and hierarchical clustering algorithms were run also in Metaboanalyst (50). Metabolomics data are presented as relative abundance values from 4-7 biological replicates. Differences were determined using Welch’s t-test where significant interactions were observed. Significance was determined at p values < 0.05. The metabolomics data for 3, MIPS-2673 and drug-free controls were reported previously (7, 51).