Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183
Name
s41467-022-29688-5.pdf
Description
Published version
Size
1.7 MB
Format
Adobe PDF
Checksum (MD5)
c6f642cf1446ee7ba2fe3106d12d8377
Author(s)
Niles, Jacquin
Date Issued
2022
Journal
Nature Communications
Publisher
Springer Science and Business Media LLC
Citation
Niles, Jacquin. 2022. "Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183." Nature Communications, 13 (1).
Version
Final published version
Abstract
AbstractDrug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as a first-in-class acetyl-CoA synthetase (AcAS) inhibitor to enter preclinical development. Our studies demonstrate attractive drug-like properties and in vivo efficacy in a humanized mouse model of Plasmodium falciparum infection. The compound shows single digit nanomolar in vitro activity against P. falciparum and P. vivax clinical isolates, and potently blocks P. falciparum transmission to Anopheles mosquitoes. Genetic and biochemical studies identify AcAS as the target of the MMV693183-derived antimetabolite, CoA-MMV693183. Pharmacokinetic-pharmacodynamic modelling predict that a single 30 mg oral dose is sufficient to cure a malaria infection in humans. Toxicology studies in rats indicate a > 30-fold safety margin in relation to the predicted human efficacious exposure. In conclusion, MMV693183 represents a promising candidate for further (pre)clinical development with a novel mode of action for treatment of malaria and blocking transmission.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Terms of Use
Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1038/S41467-022-29688-5
