Potent acyl-CoA synthetase 10 inhibitors kill Plasmodium falciparum by disrupting triglyceride formation

Selina Bopp, Charisse Flerida A. Pasaje, Robert L. Summers, Pamela Magistrado-Coxen, Kyra A. Schindler, Victoriano Corpas-Lopez, Tomas Yeo, Sachel Mok, Sumanta Dey, Sebastian Smick, Armiyaw S. Nasamu, Allison R. Demas, Rachel Milne, Natalie Wiedemar, Victoria Corey, Maria De Gracia Gomez-Lorenzo, Virginia Franco, Angela M. Early, Amanda K. Lukens, Danny Milner, Jeremy Furtado, Francisco-Javier Gamo, Elizabeth A. Winzeler, Sarah K. Volkman, Maëlle Duffey, Benoît Laleu, David A. Fidock, Susan Wyllie, Jacquin C. Niles and Dyann F. Wirth ()
Additional contact information
Selina Bopp: Harvard T.H. Chan School of Public Health
Charisse Flerida A. Pasaje: Massachusetts Institute of Technology
Robert L. Summers: Harvard T.H. Chan School of Public Health
Pamela Magistrado-Coxen: Harvard T.H. Chan School of Public Health
Kyra A. Schindler: Columbia University Irving Medical Center
Victoriano Corpas-Lopez: University of Dundee
Tomas Yeo: Columbia University Irving Medical Center
Sachel Mok: Columbia University Irving Medical Center
Sumanta Dey: Massachusetts Institute of Technology
Sebastian Smick: Massachusetts Institute of Technology
Armiyaw S. Nasamu: Massachusetts Institute of Technology
Allison R. Demas: Harvard T.H. Chan School of Public Health
Rachel Milne: University of Dundee
Natalie Wiedemar: University of Dundee
Victoria Corey: University of California, San Diego, School of Medicine
Maria De Gracia Gomez-Lorenzo: Diseases of the Developing World, GlaxoSmithKline, Tres Cantos
Virginia Franco: Diseases of the Developing World, GlaxoSmithKline, Tres Cantos
Angela M. Early: Harvard T.H. Chan School of Public Health
Amanda K. Lukens: Harvard T.H. Chan School of Public Health
Danny Milner: Harvard T.H. Chan School of Public Health
Jeremy Furtado: Harvard T.H. Chan School of Public Health
Francisco-Javier Gamo: Diseases of the Developing World, GlaxoSmithKline, Tres Cantos
Elizabeth A. Winzeler: Columbia University Irving Medical Center
Sarah K. Volkman: Harvard T.H. Chan School of Public Health
Maëlle Duffey: Medicines for Malaria Venture
Benoît Laleu: Medicines for Malaria Venture
David A. Fidock: Columbia University Irving Medical Center
Susan Wyllie: University of Dundee
Jacquin C. Niles: Massachusetts Institute of Technology
Dyann F. Wirth: Harvard T.H. Chan School of Public Health

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Identifying how small molecules act to kill malaria parasites can lead to new “chemically validated” targets. By pressuring Plasmodium falciparum asexual blood stage parasites with three novel structurally-unrelated antimalarial compounds (MMV665924, MMV019719 and MMV897615), and performing whole-genome sequence analysis on resistant parasite lines, we identify multiple mutations in the P. falciparum acyl-CoA synthetase (ACS) genes PfACS10 (PF3D7_0525100, M300I, A268D/V, F427L) and PfACS11 (PF3D7_1238800, F387V, D648Y, and E668K). Allelic replacement and thermal proteome profiling validates PfACS10 as a target of these compounds. We demonstrate that this protein is essential for parasite growth by conditional knockdown and observe increased compound susceptibility upon reduced expression. Inhibition of PfACS10 leads to a reduction in triacylglycerols and a buildup of its lipid precursors, providing key insights into its function. Analysis of the PfACS11 gene and its mutations point to a role in mediating resistance via decreased protein stability.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-023-36921-2 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36921-2

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-36921-2

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().