1. Chemogenomics identifies acetyl-coenzyme A synthetase as a target for malaria treatment and prevention.
- Author
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Summers RL, Pasaje CFA, Pisco JP, Striepen J, Luth MR, Kumpornsin K, Carpenter EF, Munro JT, Lin, Plater A, Punekar AS, Shepherd AM, Shepherd SM, Vanaerschot M, Murithi JM, Rubiano K, Akidil A, Ottilie S, Mittal N, Dilmore AH, Won M, Mandt REK, McGowen K, Owen E, Walpole C, Llinás M, Lee MCS, Winzeler EA, Fidock DA, Gilbert IH, Wirth DF, Niles JC, Baragaña B, and Lukens AK
- Subjects
- Acetate-CoA Ligase metabolism, Antimalarials chemistry, Enzyme Inhibitors chemistry, Humans, Malaria metabolism, Models, Molecular, Molecular Structure, Parasitic Sensitivity Tests, Plasmodium falciparum enzymology, Acetate-CoA Ligase antagonists & inhibitors, Antimalarials pharmacology, Enzyme Inhibitors pharmacology, Malaria drug therapy, Plasmodium falciparum drug effects
- Abstract
We identify the Plasmodium falciparum acetyl-coenzyme A synthetase (PfAcAS) as a druggable target, using genetic and chemical validation. In vitro evolution of resistance with two antiplasmodial drug-like compounds (MMV019721 and MMV084978) selects for mutations in PfAcAS. Metabolic profiling of compound-treated parasites reveals changes in acetyl-CoA levels for both compounds. Genome editing confirms that mutations in PfAcAS are sufficient to confer resistance. Knockdown studies demonstrate that PfAcAS is essential for asexual growth, and partial knockdown induces hypersensitivity to both compounds. In vitro biochemical assays using recombinantly expressed PfAcAS validates that MMV019721 and MMV084978 directly inhibit the enzyme by preventing CoA and acetate binding, respectively. Immunolocalization studies reveal that PfAcAS is primarily localized to the nucleus. Functional studies demonstrate inhibition of histone acetylation in compound-treated wild-type, but not in resistant parasites. Our findings identify and validate PfAcAS as an essential, druggable target involved in the epigenetic regulation of gene expression., Competing Interests: Declaration of interests J.C.N. is a co-inventor on a patent describing the genetically encoded protein-binding RNA aptamer technology used in this work., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2022
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