title: Sequence-selective DNA recognition and enhanced cellular up-take by peptide-steroid conjugates.
abstract: Several GCN4 bZIP TF models have previously been designed and synthesized. However, the synthetic routes towards these constructs are typically tedious and difficult. We here describe the substitution of the Leucine zipper domain of the protein by a deoxycholic acid derivative appending the two GCN4 binding region peptides through an optimized double azide-alkyne cycloaddition click reaction. In addition to achieving sequence specific dsDNA binding, we have investigated the potential of these compounds to enter cells. Confocal microscopy and flow cytometry show the beneficial influence of the steroid on cell uptake. This unique synthetic model of the bZIP TF thus combines sequence specific dsDNA binding properties with enhanced cell-uptake. Given the unique properties of deoxycholic acid and the convergent nature of the synthesis, we believe this work represents a key achievement in the field of TF mimicry.
authors.affiliation: Organic and Biomimetic Chemistry Research Group, Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281 (S4), B-9000 Ghent, Belgium. annemieke.madder@ugent.be.
authors.forename: Yara
authors.initials: Y
authors.lastname: Ruiz García
authors.affiliation: Organic and Biomimetic Chemistry Research Group, Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281 (S4), B-9000 Ghent, Belgium. annemieke.madder@ugent.be.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Iyer
authors.affiliation: Organic and Biomimetic Chemistry Research Group, Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281 (S4), B-9000 Ghent, Belgium. annemieke.madder@ugent.be.
authors.forename: Dorien
authors.initials: D
authors.lastname: Van Lysebetten
authors.affiliation: Clinical Research Center, Department of Laboratory Medicine, Karolinska University Hospital Huddinge, SE-141 86, Stockholm, Sweden. edvard.smith@ki.se.
authors.forename: Y Vladimir
authors.initials: YV
authors.lastname: Pabon
authors.affiliation: Department of Pharmaceutics, Ghent University, Harelbekestraat 72, 9000 Ghent, Belgium. br.degeest@ugent.be.
authors.forename: Benoit
authors.initials: B
authors.lastname: Louage
authors.affiliation: Department of Biosciences and Nutrition (BioNut), H2. Karolinska Institutet, Novum 141 83 Huddinge, Stockholm, Sweden. Roger.Stromberg@ki.se.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Honcharenko
authors.affiliation: Department of Pharmaceutics, Ghent University, Harelbekestraat 72, 9000 Ghent, Belgium. br.degeest@ugent.be.
authors.forename: Bruno G
authors.initials: BG
authors.lastname: De Geest
authors.affiliation: Clinical Research Center, Department of Laboratory Medicine, Karolinska University Hospital Huddinge, SE-141 86, Stockholm, Sweden. edvard.smith@ki.se.
authors.forename: C I Edvard
authors.initials: CI
authors.lastname: Smith
authors.affiliation: Department of Biosciences and Nutrition (BioNut), H2. Karolinska Institutet, Novum 141 83 Huddinge, Stockholm, Sweden. Roger.Stromberg@ki.se.
authors.forename: Roger
authors.initials: R
authors.lastname: Strömberg
authors.affiliation: Organic and Biomimetic Chemistry Research Group, Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281 (S4), B-9000 Ghent, Belgium. annemieke.madder@ugent.be.
authors.forename: Annemieke
authors.initials: A
authors.lastname: Madder
mesh_terms: D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry*; D013256:Steroids / Q000737:chemistry*
chemical_list: D010455:Peptides; D013256:Steroids; D004247:DNA