title: Design and synthesis of conformationally constrained cyclophilin inhibitors showing a cyclosporin-A phenotype in C. elegans.
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.
authors.affiliation: School of Chemistry, The University of Edinburgh, King's Buildings, West Mains Road, Edinburgh, EH9 3JJ, UK.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Dunsmore
authors.forename: Kirk J
authors.initials: KJ
authors.lastname: Malone
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Bailey
authors.forename: Martin A
authors.initials: MA
authors.lastname: Wear
authors.forename: Hannah
authors.initials: H
authors.lastname: Florance
authors.forename: Sally
authors.initials: S
authors.lastname: Shirran
authors.forename: Perdita E
authors.initials: PE
authors.lastname: Barran
authors.forename: Antony P
authors.initials: AP
authors.lastname: Page
authors.forename: Malcolm D
authors.initials: MD
authors.lastname: Walkinshaw
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Turner
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D021984:Cyclophilin A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016572:Cyclosporine; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D029742:Caenorhabditis elegans Proteins; D004791:Enzyme Inhibitors; D008024:Ligands; D054852:Small Molecule Libraries; D016572:Cyclosporine; D021984:Cyclophilin A