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Phosphopantetheinyl transferase binding and inhibition by amidino-urea and hydroxypyrimidinethione compounds.
Carivenc, Coralie; Maveyraud, Laurent; Blanger, Claire; Ballereau, Stéphanie; Roy-Camille, Coralie; Nguyen, Minh Chau; Génisson, Yves; Guilhot, Christophe; Chalut, Christian; Pedelacq, Jean-Denis; Mourey, Lionel.
Affiliation
  • Carivenc C; Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, 31077, Toulouse, France.
  • Maveyraud L; Centre de Biochimie Structurale, CBS, CNRS, INSERM, Université de Montpellier, 34090, Montpellier, France.
  • Blanger C; Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, 31077, Toulouse, France.
  • Ballereau S; Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique, LSPCMIB, Université de Toulouse, CNRS, UPS, 31062, Toulouse, France.
  • Roy-Camille C; Evotec (France), 31100, Toulouse, France.
  • Nguyen MC; Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique, LSPCMIB, Université de Toulouse, CNRS, UPS, 31062, Toulouse, France.
  • Génisson Y; Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, 31077, Toulouse, France.
  • Guilhot C; Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, 31077, Toulouse, France.
  • Chalut C; Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, USA.
  • Pedelacq JD; Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique, LSPCMIB, Université de Toulouse, CNRS, UPS, 31062, Toulouse, France.
  • Mourey L; Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, 31077, Toulouse, France.
Sci Rep ; 11(1): 18042, 2021 09 10.
Article in En | MEDLINE | ID: mdl-34508141
Owing to their role in activating enzymes essential for bacterial viability and pathogenicity, phosphopantetheinyl transferases represent novel and attractive drug targets. In this work, we examined the inhibitory effect of the aminido-urea 8918 compound against the phosphopantetheinyl transferases PptAb from Mycobacterium abscessus and PcpS from Pseudomonas aeruginosa, two pathogenic bacteria associated with cystic fibrosis and bronchiectasis, respectively. Compound 8918 exhibits inhibitory activity against PptAb but displays no activity against PcpS in vitro, while no antimicrobial activity against Mycobacterium abscessus or Pseudomonas aeruginosa could be detected. X-ray crystallographic analysis of 8918 bound to PptAb-CoA alone and in complex with an acyl carrier protein domain in addition to the crystal structure of PcpS in complex with CoA revealed the structural basis for the inhibition mechanism of PptAb by 8918 and its ineffectiveness against PcpS. Finally, in crystallo screening of potent inhibitors from the National Cancer Institute library identified a hydroxypyrimidinethione derivative that binds PptAb. Both compounds could serve as scaffolds for the future development of phosphopantetheinyl transferases inhibitors.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pyrimidinones / Bacterial Proteins / Urea / Transferases (Other Substituted Phosphate Groups) / Enzyme Inhibitors Language: En Journal: Sci Rep Year: 2021 Document type: Article Affiliation country: France Country of publication: United kingdom

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pyrimidinones / Bacterial Proteins / Urea / Transferases (Other Substituted Phosphate Groups) / Enzyme Inhibitors Language: En Journal: Sci Rep Year: 2021 Document type: Article Affiliation country: France Country of publication: United kingdom