title: Toward targeted oral vaccine delivery systems: selection of lectin mimetics from combinatorial libraries.
abstract: OBJECTIVE
  Various lectins bind specifically to oligosaccharides on intestinal cells. Exploiting this specificity, Ulex europaeus agglutinin I (UEA1) has been used as a ligand for targeted oral vaccine delivery to M cells (antigen-presenting cells) in follicle-associated epithelium. In this study we characterized compounds identified from mixture-based positional scanning synthetic combinatorial libraries, which mimic UEA1 and, thus, may have properties applicable to targeted drug delivery.
  
  
  METHODS
  Two UEA1 mimetics were synthesized and their activity was verified on live cells. The ability of the lead compound, a tetragalloyl D-Lysine amide construct (4-copy gallic acid construct), to deliver dye-loaded polystyrene particles to M cells was assessed in an in situ mouse gut loop model.
  
  
  RESULTS
  The 4-copy gallic acid construct inhibited UEA1 binding to Caco-2 cell membranes with an IC50 of 3 microM, a 650- to 5000-fold increase over the natural UEA1 substrate alpha-L-fucose. The biotin-labeled derivative of this construct demonstrated comparable binding activity as verified on live cells by fluorescence-activated cell sorting. Preclinical studies confirmed its ability to mediate M cell-specific delivery of streptavidin-coated particles in vivo.
  
  
  CONCLUSIONS
  Polyphenolic compounds, D-Lysine scaffolds with multiple galloyl groups, can mimic functional activities of UEA1. Properties of such molecules, including low molecular weight, stability, ease of synthesis and low cost, highlight their potential for application in targeted vaccine delivery.
authors.affiliation: Elan Drug Delivery, Biotechnology Building, Trinity College, Dublin 2, Ireland. ilambkin@eircom.net
authors.forename: Imelda
authors.initials: I
authors.lastname: Lambkin
authors.forename: Clemencia
authors.initials: C
authors.lastname: Pinilla
authors.forename: Christa
authors.initials: C
authors.lastname: Hamashin
authors.forename: Lisa
authors.initials: L
authors.lastname: Spindler
authors.forename: Shannon
authors.initials: S
authors.lastname: Russell
authors.forename: Amy
authors.initials: A
authors.lastname: Schink
authors.forename: Rosa
authors.initials: R
authors.lastname: Moya-Castro
authors.forename: Gina
authors.initials: G
authors.lastname: Allicotti
authors.forename: Lisa
authors.initials: L
authors.lastname: Higgins
authors.forename: Melanie
authors.initials: M
authors.lastname: Smith
authors.forename: Jackie
authors.initials: J
authors.lastname: Dee
authors.forename: Carolyn
authors.initials: C
authors.lastname: Wilson
authors.forename: Richard
authors.initials: R
authors.lastname: Houghten
authors.forename: Daniel
authors.initials: D
authors.lastname: O'Mahony
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018938:Caco-2 Cells; D002462:Cell Membrane / Q000378:metabolism; D020650:Combinatorial Chemistry Techniques; D004337:Drug Carriers; D005707:Gallic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D018716:Molecular Mimicry; D019151:Peptide Library; D037121:Plant Lectins / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011137:Polystyrenes / Q000737:chemistry; D011485:Protein Binding; D019809:Streptavidin / Q000008:administration & dosage; D013329:Structure-Activity Relationship; D014612:Vaccines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D004337:Drug Carriers; D019151:Peptide Library; D037121:Plant Lectins; D011137:Polystyrenes; C036850:Ulex europaeus lectins; D014612:Vaccines; D005707:Gallic Acid; D019809:Streptavidin