title: Small-molecule mimics of an alpha-helix for efficient transport of proteins into cells.
abstract: We designed and synthesized small-molecule mimics of an alpha-helical peptide protein transduction domain (PTD). These small-molecule carriers, which we termed SMoCs, are easily coupled to biomolecules, and efficiently deliver dye molecules and recombinant proteins into a variety of cell types. We designed the SMoCs using molecular modeling techniques. As an example of a protein cargo, we applied this new technology to the internalization of the DNA replication licensing repressor geminin, in vitro, providing evidence that extracellularly delivered SMoC-geminin can have an antiproliferative effect on human cancer cells. Uptake of SMoC-geminin was inhibited at 4 degrees C and by chlorpromazine, a compound that induces misassembly of clathrin-coated pits at the cell surface. Thus the mechanism of uptake is likely to be clathrin-mediated endocytosis.
authors.affiliation: Biological and Medicinal Chemistry Group, Wolfson Institute for Biomedical Research, University College London, Gower Street, London, WC1E 6BT, UK.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Okuyama
authors.forename: Heike
authors.initials: H
authors.lastname: Laman
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Kingsbury
authors.forename: Cristina
authors.initials: C
authors.lastname: Visintin
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Leo
authors.forename: Kathryn Leigh
authors.initials: KL
authors.lastname: Eward
authors.forename: Kai
authors.initials: K
authors.lastname: Stoeber
authors.forename: Chris
authors.initials: C
authors.lastname: Boshoff
authors.forename: Gareth H
authors.initials: GH
authors.lastname: Williams
authors.forename: David L
authors.initials: DL
authors.lastname: Selwood
mesh_terms: D000818:Animals; D051943:Antennapedia Homeodomain Protein / Q000737:chemistry; D001713:Biphenyl Compounds; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002966:Clathrin / Q000378:metabolism; D003034:Coated Pits, Cell-Membrane / Q000737:chemistry; D004396:Coloring Agents / Q000737:chemistry / Q000378:metabolism; D004705:Endocytosis; D064248:Geminin; D006367:HeLa Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D018716:Molecular Mimicry; D041681:NIH 3T3 Cells; D010455:Peptides / Q000737:chemistry; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021381:Protein Transport
chemical_list: D051943:Antennapedia Homeodomain Protein; D001713:Biphenyl Compounds; D018797:Cell Cycle Proteins; D002966:Clathrin; D004396:Coloring Agents; D064248:Geminin; D010455:Peptides; C577995:GMNN protein, human; C010574:biphenyl