Design and Synthesis of Conformationally Constrained Cyclophilin Inhibitors Showing a Cyclosporin-A Phenotype in C. elegans

C. J. Dunsmore, K. J. Malone, K. R. Bailey, M. A. Wear, H. Florance, S. Shirran, P. E. Barran, A. P. Page, M. D. Walkinshaw, N. J. Turner

Research output: Contribution to journalArticlepeer-review

Abstract

Cyclophilin A (CypA) is a member of the immunophilin family of proteins and receptor for the immunosuppressant drug cyclosporin A (CsA). Here we describe the design and synthesis of a new class of small-molecule inhibitors for CypA that are based upon a dimedone template. Electrospray mass spectrometry is utilised as an initial screen to quantify the protein affinity of the ligands. Active inhibitors and fluorescently labelled derivatives are then used as chemical probes for investigating the biological role of cyclophilins in the nematode Caenorhabditis elegans.
Original languageEnglish
Pages (from-to)802-810
Number of pages9
JournalChemBioChem
Volume12
Issue number5
DOIs
Publication statusPublished - Mar 2011

Keywords

  • Small Molecule Libraries
  • Spectrometry, Mass, Electrospray Ionization
  • Animals
  • Caenorhabditis elegans Proteins
  • Cyclosporine
  • Models, Molecular
  • Caenorhabditis elegans
  • Enzyme Inhibitors
  • Protein Binding
  • Drug Design
  • Ligands
  • Cyclophilin A

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