Evidence map›Paper›PMID 34348113›Full record

ArticleCell chemical biology2022

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 and 24 more

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell chemical biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.

0numbers the graph read from it
0cells of the map it votes in
41citing papers in PubMed
12.8field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

41 citing papers in PubMed, 77 citations in OpenAlex.

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  19. A Drug Repurposing Approach Reveals Targetable Epigenetic Pathways inbioRxiv : the preprint server for biology · 2024
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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

34 authors at 10 institutions in 4 countries.

Robert L SummersDepartment of Immunology & Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Research School of Biology, Australian National University, Canberra, ACT 2601, Australia.
Charisse Flerida A PasajeDepartment of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Joao P PiscoWellcome Centre for Anti-Infectives Research, Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 5EH, UK.
Josefine StriepenDepartment of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA.
Madeline R LuthDepartment of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.
Krittikorn KumpornsinWellcome Sanger Institute, Hinxton CB10 1SA, UK.
Emma F CarpenterWellcome Sanger Institute, Hinxton CB10 1SA, UK.
Justin T MunroDepartment of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA; Huck Center for Malaria Research, The Pennsylvania State University, University Park, PA 16802, USA.
De LinWellcome Centre for Anti-Infectives Research, Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 5EH, UK.
Andrew PlaterWellcome Centre for Anti-Infectives Research, Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 5EH, UK.
Avinash S PunekarWellcome Centre for Anti-Infectives Research, Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 5EH, UK.
Andrew M ShepherdWellcome Centre for Anti-Infectives Research, Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 5EH, UK.
Sharon M ShepherdWellcome Centre for Anti-Infectives Research, Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 5EH, UK.
Manu VanaerschotDepartment of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA.
James M MurithiDepartment of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA.
Kelly RubianoDepartment of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA.
Aslı AkidilWellcome Sanger Institute, Hinxton CB10 1SA, UK.
Sabine OttilieDepartment of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.
Nimisha MittalDepartment of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.
A Hazel DilmoreDepartment of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.
Madalyn WonDepartment of Immunology & Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
Rebecca E K MandtDepartment of Immunology & Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
Kerry McGowenDepartment of Immunology & Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
Edward OwenHuck Center for Malaria Research, The Pennsylvania State University, University Park, PA 16802, USA; Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA.
Chris WalpoleStructural Genomics Consortium, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
Manuel LlinásDepartment of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA; Huck Center for Malaria Research, The Pennsylvania State University, University Park, PA 16802, USA; Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA.
Marcus C S LeeWellcome Sanger Institute, Hinxton CB10 1SA, UK.
Elizabeth A WinzelerDepartment of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.
David A FidockDepartment of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA; Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA.
Ian H GilbertWellcome Centre for Anti-Infectives Research, Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 5EH, UK.
Dyann F WirthDepartment of Immunology & Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Infectious Disease and Microbiome Program, The Broad Institute, Cambridge, MA 02142, USA.
Jacquin C NilesDepartment of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Infectious Disease and Microbiome Program, The Broad Institute, Cambridge, MA 02142, USA.
Beatriz BaragañaWellcome Centre for Anti-Infectives Research, Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 5EH, UK. Electronic address: b.baragana@dundee.ac.uk.
Amanda K LukensDepartment of Immunology & Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Infectious Disease and Microbiome Program, The Broad Institute, Cambridge, MA 02142, USA. Electronic address: alukens@broadinstitute.org.
University of Dundee · GBColumbia University Irving Medical Center · USUniversity of California San Diego · USWellcome Sanger Institute · GBBroad Institute · USHarvard University · USPennsylvania State University · USAustralian National University · AUMassachusetts Institute of Technology · USMcGill University Health Centre · CA

Funding

Training Program in Basic Clinical GeneticsT32GM008666 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI HAMILTON, BRUCE A · 1998 to 2021
$8.6M
Defining the resistome in P. falciparum: evolution and mechanismR01AI169892 · NIAID · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI Daniel E. Goldberg, Elizabeth A Winzeler · 2023 to 2026
$4.4M
Discovery of chemically validated malaria liver stage targetsR01AI090141 · NIAID · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI WINZELER, ELIZABETH A · 2011 to 2019
$3.4M
Integrative Analysis of Metabolic Phenotypes (IAMP) Predoctoral Training ProgramT32DK120509 · NIDDK · PENNSYLVANIA STATE UNIVERSITY, THE · PI PATTERSON, ANDREW, PERDEW, GARY H. · 2020 to 2024
$781k
NIAID NIH HHS R01 AI090141NIAID NIH HHS R01 AI169892NIDDK NIH HHS T32 DK120509NIGMS NIH HHS T32 GM008666Wellcome TrustWellcome Trust 203134/Z/16/ZWellcome Trust 206194
6 · The paper itself

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.

Indexed as

Acetate-CoA LigaseAntimalarialsEnzyme InhibitorsHumansMalariaModels, MolecularMolecular StructureParasitic Sensitivity TestsPlasmodium falciparumAcetate-CoA LigaseAntimalarialsEnzyme Inhibitorsacetyl-CoA synthetaseantimalarialdrug developmentdrug target identificationhistone acetylationmalariamechanism of actionPlasmodium falciparum

Identifiers

PMID34348113
PMCPMC8878317
OpenAlexW3191673291

What Socratic holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.