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; Dyann F. Wirth

doi:10.1038/s41467-023-36921-2

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, Dyann F. Wirth (Lead / Corresponding author)

Biological Chemistry and Drug Discovery

Research output: Contribution to journal › Article › peer-review

22 Citations (Scopus)

145 Downloads (Pure)

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.

Original language	English
Article number	1455
Number of pages	15
Journal	Nature Communications
Volume	14
DOIs	https://doi.org/10.1038/s41467-023-36921-2
Publication status	Published - 16 Mar 2023

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Malaria
Parasite biology
Pathogens

ASJC Scopus subject areas

General
General Physics and Astronomy
General Chemistry
General Biochemistry,Genetics and Molecular Biology

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10.1038/s41467-023-36921-2Licence: CC BY

Final Published VersionFinal published version, 11.9 MBLicence: CC BY

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Bopp, S., Pasaje, C. F. A., Summers, R. L., Magistrado-Coxen, P., Schindler, K. A., Corpas-Lopez, V., Yeo, T., Mok, S., Dey, S., Smick, S., Nasamu, A. S., Demas, A. R., Milne, R., Wiedemar, N., Corey, V., Gomez-Lorenzo, M. D. G., Franco, V., Early, A. M., Lukens, A. K., ... Wirth, D. F. (2023). Potent acyl-CoA synthetase 10 inhibitors kill Plasmodium falciparum by disrupting triglyceride formation. Nature Communications, 14, Article 1455. https://doi.org/10.1038/s41467-023-36921-2

@article{4a287aee56e340a3abd904c863c93191,

title = "Potent acyl-CoA synthetase 10 inhibitors kill Plasmodium falciparum by disrupting triglyceride formation",

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. ",

keywords = "Malaria, Parasite biology, Pathogens",

author = "Selina Bopp and Pasaje, \{Charisse Flerida A.\} and Summers, \{Robert L.\} and Pamela Magistrado-Coxen and Schindler, \{Kyra A.\} and Victoriano Corpas-Lopez and Tomas Yeo and Sachel Mok and Sumanta Dey and Sebastian Smick and Nasamu, \{Armiyaw S.\} and Demas, \{Allison R.\} and Rachel Milne and Natalie Wiedemar and Victoria Corey and Gomez-Lorenzo, \{Maria De Gracia\} and Virginia Franco and Early, \{Angela M.\} and Lukens, \{Amanda K.\} and Danny Milner and Jeremy Furtado and Gamo, \{Francisco Javier\} and Winzeler, \{Elizabeth A.\} and Volkman, \{Sarah K.\} and Ma{\"e}lle Duffey and Beno{\^i}t Laleu and Fidock, \{David A.\} and Susan Wyllie and Niles, \{Jacquin C.\} and Wirth, \{Dyann F.\}",

note = "Funding Information: Bill and Melinda Gates Foundation grant OPP1156051 to DFW and grant OPP1054480 to EAW. Medicines for Malaria Venture (MMV08/0015) and NIH (R37 AI050234) to DAF. Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = mar,

day = "16",

doi = "10.1038/s41467-023-36921-2",

language = "English",

volume = "14",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

Bopp, S, Pasaje, CFA, Summers, RL, Magistrado-Coxen, P, Schindler, KA, Corpas-Lopez, V, Yeo, T, Mok, S, Dey, S, Smick, S, Nasamu, AS, Demas, AR, Milne, R, Wiedemar, N, Corey, V, Gomez-Lorenzo, MDG, Franco, V, Early, AM, Lukens, AK, Milner, D, Furtado, J, Gamo, FJ, Winzeler, EA, Volkman, SK, Duffey, M, Laleu, B, Fidock, DA, Wyllie, S, Niles, JC & Wirth, DF 2023, 'Potent acyl-CoA synthetase 10 inhibitors kill Plasmodium falciparum by disrupting triglyceride formation', Nature Communications, vol. 14, 1455. https://doi.org/10.1038/s41467-023-36921-2

TY - JOUR

T1 - Potent acyl-CoA synthetase 10 inhibitors kill Plasmodium falciparum by disrupting triglyceride formation

AU - Bopp, Selina

AU - Pasaje, Charisse Flerida A.

AU - Summers, Robert L.

AU - Magistrado-Coxen, Pamela

AU - Schindler, Kyra A.

AU - Corpas-Lopez, Victoriano

AU - Yeo, Tomas

AU - Mok, Sachel

AU - Dey, Sumanta

AU - Smick, Sebastian

AU - Nasamu, Armiyaw S.

AU - Demas, Allison R.

AU - Milne, Rachel

AU - Wiedemar, Natalie

AU - Corey, Victoria

AU - Gomez-Lorenzo, Maria De Gracia

AU - Franco, Virginia

AU - Early, Angela M.

AU - Lukens, Amanda K.

AU - Milner, Danny

AU - Furtado, Jeremy

AU - Gamo, Francisco Javier

AU - Winzeler, Elizabeth A.

AU - Volkman, Sarah K.

AU - Duffey, Maëlle

AU - Laleu, Benoît

AU - Fidock, David A.

AU - Wyllie, Susan

AU - Niles, Jacquin C.

AU - Wirth, Dyann F.

N1 - Funding Information: Bill and Melinda Gates Foundation grant OPP1156051 to DFW and grant OPP1054480 to EAW. Medicines for Malaria Venture (MMV08/0015) and NIH (R37 AI050234) to DAF. Copyright: © 2023, The Author(s).

PY - 2023/3/16

Y1 - 2023/3/16

N2 - 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.

AB - 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.

KW - Malaria

KW - Parasite biology

KW - Pathogens

UR - https://www.scopus.com/pages/publications/85150313946

U2 - 10.1038/s41467-023-36921-2

DO - 10.1038/s41467-023-36921-2

M3 - Article

C2 - 36927839

AN - SCOPUS:85150313946

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

M1 - 1455

ER -

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

Abstract

UN SDGs

Keywords

ASJC Scopus subject areas

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