Summary of project PR002199
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 PR002199. The data can be accessed directly via it's Project DOI: 10.21228/M8CN7H This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
| Project ID: | PR002199 |
| Project DOI: | doi: 10.21228/M8CN7H |
| Project Title: | Optimization and characterization of N-acetamide indoles as antimalarials that target the Plasmodium falciparum protein, PfATP4 |
| Project Summary: | Emerging resistance to frontline antimalarials is resulting in them becoming increasingly ineffective, highlighting the need for new antimalarials. To discover new antimalarials a screen of the Janssen Jumpstarter library against the asexual stage parasite uncovered an N-acetamide indole hit class. The structure-activity relationship of this chemotype was defined by generating optimized frontrunner analogs including WJM664 with potent asexual stage activity and high metabolic stability. To determine the mechanism of action, resistance was selected and whole genome sequencing revealed mutations in PfATP4. PfATP4 was validated as the target of the N-acetamide indole class showing cross-resistance to PfATP4 drug-resistant strains, and a metabolomic signature consistent with the PfATP4 inhibitor KAE609. The indole acetamide class exhibited a fast-to-moderate rate of kill and a vacuolized asexual blood stage phenotype, phenocopying known PfATP4 inhibitors. Moreover, N-acetamide indole analogs increased cytosolic Na+ demonstrating on-target inhibition of PfATP4. N-Acetamide indole derivatives inhibited male and female gamete development and blocked transmission from infected blood to the mosquito. WJM664 exhibited low oral efficacy in an asexual stage P. berghei mouse model which may be attributed to the low potency against PbATP4, and the low aqueous solubility and Caco-2 permeability. Further optimization of these attributes is required for the N-acetamide indole class to be considered for development in a curative or transmission blocking combination therapy. |
| Institute: | Monash University |
| Last Name: | Giannangelo |
| First Name: | Carlo |
| Address: | 381 Royal Parade, Parkville, Victoria, 3052, Australia |
| Email: | carlo.giannangelo@monash.edu |
| Phone: | 99039282 |
Summary of all studies in project PR002199
| Study ID | Study Title | Species | Institute | Analysis(* : Contains Untargted data) | Release Date | Version | Samples | Download(* : Contains raw data) |
|---|---|---|---|---|---|---|---|---|
| ST003565 | Metaboloomics analysis of the antimalarial compound WEHI-1888504 (aka compound 59) in Plasmodium falciparum (3D7) infected red blood cells | Plasmodium falciparum | Monash University | MS | 2024-12-02 | 1 | 13 | Uploaded data (1.8G)* |
