Your browser doesn't support javascript.
loading
Chemogenomics identifies acetyl-coenzyme A synthetase as a target for malaria treatment and prevention.
Summers, Robert L; Pasaje, Charisse Flerida A; Pisco, Joao P; Striepen, Josefine; Luth, Madeline R; Kumpornsin, Krittikorn; Carpenter, Emma F; Munro, Justin T; Lin, De; Plater, Andrew; Punekar, Avinash S; Shepherd, Andrew M; Shepherd, Sharon M; Vanaerschot, Manu; Murithi, James M; Rubiano, Kelly; Akidil, Asli; Ottilie, Sabine; Mittal, Nimisha; Dilmore, A Hazel; Won, Madalyn; Mandt, Rebecca E K; McGowen, Kerry; Owen, Edward; Walpole, Chris; Llinás, Manuel; Lee, Marcus C S; Winzeler, Elizabeth A; Fidock, David A; Gilbert, Ian H; Wirth, Dyann F; Niles, Jacquin C; Baragaña, Beatriz; Lukens, Amanda K.
Afiliación
  • Summers RL; Department 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.
  • Pasaje CFA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Pisco JP; Wellcome Centre for Anti-Infectives Research, Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 5EH, UK.
  • Striepen J; Department of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA.
  • Luth MR; Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.
  • Kumpornsin K; Wellcome Sanger Institute, Hinxton CB10 1SA, UK.
  • Carpenter EF; Wellcome Sanger Institute, Hinxton CB10 1SA, UK.
  • Munro JT; Department 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.
  • Lin; Wellcome Centre for Anti-Infectives Research, Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 5EH, UK.
  • Plater A; Wellcome Centre for Anti-Infectives Research, Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 5EH, UK.
  • Punekar AS; Wellcome Centre for Anti-Infectives Research, Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 5EH, UK.
  • Shepherd AM; Wellcome Centre for Anti-Infectives Research, Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 5EH, UK.
  • Shepherd SM; Wellcome Centre for Anti-Infectives Research, Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 5EH, UK.
  • Vanaerschot M; Department of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA.
  • Murithi JM; Department of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA.
  • Rubiano K; Department of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA.
  • Akidil A; Wellcome Sanger Institute, Hinxton CB10 1SA, UK.
  • Ottilie S; Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.
  • Mittal N; Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.
  • Dilmore AH; Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.
  • Won M; Department of Immunology & Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
  • Mandt REK; Department of Immunology & Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
  • McGowen K; Department of Immunology & Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
  • Owen E; 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.
  • Walpole C; Structural Genomics Consortium, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
  • Llinás M; Department 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 16
  • Lee MCS; Wellcome Sanger Institute, Hinxton CB10 1SA, UK.
  • Winzeler EA; Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.
  • Fidock DA; Department 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.
  • Gilbert IH; Wellcome Centre for Anti-Infectives Research, Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 5EH, UK.
  • Wirth DF; Department 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.
  • Niles JC; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Infectious Disease and Microbiome Program, The Broad Institute, Cambridge, MA 02142, USA.
  • Baragaña B; Wellcome 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.
  • Lukens AK; Department 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.
Cell Chem Biol ; 29(2): 191-201.e8, 2022 02 17.
Article en En | MEDLINE | ID: mdl-34348113
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.
Asunto(s)
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Plasmodium falciparum / Acetato CoA Ligasa / Inhibidores Enzimáticos / Malaria / Antimaláricos Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Cell Chem Biol Año: 2022 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Plasmodium falciparum / Acetato CoA Ligasa / Inhibidores Enzimáticos / Malaria / Antimaláricos Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Cell Chem Biol Año: 2022 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos