Chemogenomics identifies acetyl-coenzyme A synthetase as a target for malaria treatment and prevention

Robert L. Summers; Charisse Flerida A. Pasaje; Joao P. Pisco; Josefine Striepen; Madeline R. Luth; Krittikorn Kumpornsin; Emma F. Carpenter; Justin T. Munro; De Lin; Andrew Plater; Avinash S. Punekar; Andrew M. Shepherd; Sharon M. Shepherd; Manu Vanaerschot; James M. Murithi; Kelly Rubiano; Aslı Akidil; Sabine Ottilie; Nimisha Mittal; A. Hazel Dilmore; Madalyn Won; Rebecca E. K. Mandt; Kerry McGowen; Edward Owen; Chris Walpole; Manuel Llinás; Marcus C. S. Lee; Elizabeth A. Winzeler; David A. Fidock; Ian H. Gilbert; Dyann F. Wirth; Jacquin C. Niles; Beatriz Baragaña; Amanda K. Lukens

doi:10.1016/j.chembiol.2021.07.010

Chemogenomics identifies acetyl-coenzyme A synthetase as a target for malaria treatment and prevention

Robert L. Summers, Charisse Flerida A. Pasaje, Joao P. Pisco, Josefine Striepen, Madeline R. Luth, Krittikorn Kumpornsin, Emma F. Carpenter, Justin T. Munro, De Lin, Andrew Plater, Avinash S. Punekar, Andrew M. Shepherd, Sharon M. Shepherd, Manu Vanaerschot, James M. Murithi, Kelly Rubiano, Aslı Akidil, Sabine Ottilie, Nimisha Mittal, A. Hazel DilmoreMadalyn Won, Rebecca E. K. Mandt, Kerry McGowen, Edward Owen, Chris Walpole, Manuel Llinás, Marcus C. S. Lee, Elizabeth A. Winzeler, David A. Fidock, Ian H. Gilbert, Dyann F. Wirth, Jacquin C. Niles, Beatriz Baragaña (Lead / Corresponding author), Amanda K. Lukens (Lead / Corresponding author)

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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.

Original language	English
Article number	E8
Pages (from-to)	191-201.e8
Number of pages	20
Journal	Cell Chemical Biology
Volume	29
Issue number	2
Early online date	28 Jul 2021
DOIs	https://doi.org/10.1016/j.chembiol.2021.07.010
Publication status	Published - 17 Feb 2022

Keywords

malaria
drug target identification
antimalarial
drug development
acetyl-CoA synthetase
Plasmodium falciparum
mechanism of action
histone acetylation

ASJC Scopus subject areas

Drug Discovery
Molecular Medicine
Molecular Biology
Biochemistry
Clinical Biochemistry
Pharmacology

UN SDGs

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

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10.1016/j.chembiol.2021.07.010Licence: CC BY

Final Published VersionFinal published version, 2.87 MBLicence: CC BY

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Summers, R. L., Pasaje, C. F. A., Pisco, J. P., Striepen, J., Luth, M. R., Kumpornsin, K., Carpenter, E. F., Munro, J. T., Lin, D., Plater, A., Punekar, A. S., Shepherd, A. M., Shepherd, S. M., Vanaerschot, M., Murithi, J. M., Rubiano, K., Akidil, A., Ottilie, S., Mittal, N., ... Lukens, A. K. (2022). Chemogenomics identifies acetyl-coenzyme A synthetase as a target for malaria treatment and prevention. Cell Chemical Biology, 29(2), 191-201.e8. Article E8. https://doi.org/10.1016/j.chembiol.2021.07.010

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title = "Chemogenomics identifies acetyl-coenzyme A synthetase as a target for malaria treatment and prevention",

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.",

keywords = "malaria, drug target identification, antimalarial, drug development, acetyl-CoA synthetase, Plasmodium falciparum, mechanism of action, histone acetylation",

author = "Summers, {Robert L.} and Pasaje, {Charisse Flerida A.} and Pisco, {Joao P.} and Josefine Striepen and Luth, {Madeline R.} and Krittikorn Kumpornsin and Carpenter, {Emma F.} and Munro, {Justin T.} and De Lin and Andrew Plater and Punekar, {Avinash S.} and Shepherd, {Andrew M.} and Shepherd, {Sharon M.} and Manu Vanaerschot and Murithi, {James M.} and Kelly Rubiano and Aslı Akidil and Sabine Ottilie and Nimisha Mittal and Dilmore, {A. Hazel} and Madalyn Won and Mandt, {Rebecca E. K.} and Kerry McGowen and Edward Owen and Chris Walpole and Manuel Llin{\'a}s and Lee, {Marcus C. S.} and Winzeler, {Elizabeth A.} and Fidock, {David A.} and Gilbert, {Ian H.} and Wirth, {Dyann F.} and Niles, {Jacquin C.} and Beatriz Baraga{\~n}a and Lukens, {Amanda K.}",

note = "Funding Information: We thank the Bill and Melinda Gates Foundation (grant OPP1032548 to the Structure-guided Drug Discovery Coalition— SDDC, OPP1162467 to J.C.N. and OPP1054480 to E.A.W.) and the Global Health Innovative Technology Fund Fund (GHIT product development portfolio grant G2018-202 to the Medicines for Malaria Venture) and the Medicines for Malaria Venture for financial support. The University of Dundee is supported by a Wellcome Trust Center Award ( 203134/Z/16/Z ). M.C.S.L. gratefully acknowledges funding from Wellcome ( 206194 ) and the Bill & Melinda Gates Foundation . D.A.F. gratefully acknowledges funding from the Medicines for Malaria Venture and the Bill & Melinda Gates Foundation . R.L.S. was supported by the Australian National Health and Medical Research Council (fellowship 1120690 ). M.R.L. was supported in part by a Ruth L. Kirschstein Institutional National Research Award from the National Institute of General Medical Sciences ( T32 GM008666 ), and. J.T.M. was supported in part by the NIH ( T32 DK120509 ). Copyright: {\textcopyright} 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.",

year = "2022",

month = feb,

day = "17",

doi = "10.1016/j.chembiol.2021.07.010",

language = "English",

volume = "29",

pages = "191--201.e8",

journal = "Cell Chemical Biology",

issn = "2451-9448",

publisher = "Elsevier",

number = "2",

}

Summers, RL, Pasaje, CFA, Pisco, JP, Striepen, J, Luth, MR, Kumpornsin, K, Carpenter, EF, Munro, JT, Lin, D , 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 & Lukens, AK 2022, 'Chemogenomics identifies acetyl-coenzyme A synthetase as a target for malaria treatment and prevention', Cell Chemical Biology, vol. 29, no. 2, E8, pp. 191-201.e8. https://doi.org/10.1016/j.chembiol.2021.07.010

TY - JOUR

T1 - Chemogenomics identifies acetyl-coenzyme A synthetase as a target for malaria treatment and prevention

AU - Summers, Robert L.

AU - Pasaje, Charisse Flerida A.

AU - Pisco, Joao P.

AU - Striepen, Josefine

AU - Luth, Madeline R.

AU - Kumpornsin, Krittikorn

AU - Carpenter, Emma F.

AU - Munro, Justin T.

AU - Lin, De

AU - Plater, Andrew

AU - Punekar, Avinash S.

AU - Shepherd, Andrew M.

AU - Shepherd, Sharon M.

AU - Vanaerschot, Manu

AU - Murithi, James M.

AU - Rubiano, Kelly

AU - Akidil, Aslı

AU - Ottilie, Sabine

AU - Mittal, Nimisha

AU - Dilmore, A. Hazel

AU - Won, Madalyn

AU - Mandt, Rebecca E. K.

AU - McGowen, Kerry

AU - Owen, Edward

AU - Walpole, Chris

AU - Llinás, Manuel

AU - Lee, Marcus C. S.

AU - Winzeler, Elizabeth A.

AU - Fidock, David A.

AU - Gilbert, Ian H.

AU - Wirth, Dyann F.

AU - Niles, Jacquin C.

AU - Baragaña, Beatriz

AU - Lukens, Amanda K.

N1 - Funding Information: We thank the Bill and Melinda Gates Foundation (grant OPP1032548 to the Structure-guided Drug Discovery Coalition— SDDC, OPP1162467 to J.C.N. and OPP1054480 to E.A.W.) and the Global Health Innovative Technology Fund Fund (GHIT product development portfolio grant G2018-202 to the Medicines for Malaria Venture) and the Medicines for Malaria Venture for financial support. The University of Dundee is supported by a Wellcome Trust Center Award ( 203134/Z/16/Z ). M.C.S.L. gratefully acknowledges funding from Wellcome ( 206194 ) and the Bill & Melinda Gates Foundation . D.A.F. gratefully acknowledges funding from the Medicines for Malaria Venture and the Bill & Melinda Gates Foundation . R.L.S. was supported by the Australian National Health and Medical Research Council (fellowship 1120690 ). M.R.L. was supported in part by a Ruth L. Kirschstein Institutional National Research Award from the National Institute of General Medical Sciences ( T32 GM008666 ), and. J.T.M. was supported in part by the NIH ( T32 DK120509 ). Copyright: © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.

PY - 2022/2/17

Y1 - 2022/2/17

N2 - 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.

AB - 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.

KW - malaria

KW - drug target identification

KW - antimalarial

KW - drug development

KW - acetyl-CoA synthetase

KW - Plasmodium falciparum

KW - mechanism of action

KW - histone acetylation

UR - http://www.scopus.com/inward/record.url?scp=85116027729&partnerID=8YFLogxK

U2 - 10.1016/j.chembiol.2021.07.010

DO - 10.1016/j.chembiol.2021.07.010

M3 - Article

C2 - 34348113

SN - 2451-9448

VL - 29

SP - 191-201.e8

JO - Cell Chemical Biology

JF - Cell Chemical Biology

IS - 2

M1 - E8

ER -

Chemogenomics identifies acetyl-coenzyme A synthetase as a target for malaria treatment and prevention

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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Wellcome Centre for Anti-Infectives Research

Cite this

Chemogenomics identifies acetyl-coenzyme A synthetase as a target for malaria treatment and prevention

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Projects

Wellcome Centre for Anti-Infectives Research

Cite this