title: Inhibition of RNA polymerase II transcription in human cells by synthetic DNA-binding ligands.
abstract: Sequence-specific DNA-binding small molecules that can permeate human cells potentially could regulate transcription of specific genes. Multiple cellular DNA-binding transcription factors are required by HIV type 1 for RNA synthesis. Two pyrrole-imidazole polyamides were designed to bind DNA sequences immediately adjacent to binding sites for the transcription factors Ets-1, lymphoid-enhancer binding factor 1, and TATA-box binding protein. These synthetic ligands specifically inhibit DNA-binding of each transcription factor and HIV type 1 transcription in cell-free assays. When used in combination, the polyamides inhibit virus replication by >99% in isolated human peripheral blood lymphocytes, with no detectable cell toxicity. The ability of small molecules to target predetermined DNA sequences located within RNA polymerase II promoters suggests a general approach for regulation of gene expression, as well as a mechanism for the inhibition of viral replication.
authors.affiliation: Department of Molecular Biology, Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Dickinson
authors.forename: R J
authors.initials: RJ
authors.lastname: Gulizia
authors.forename: J W
authors.initials: JW
authors.lastname: Trauger
authors.forename: E E
authors.initials: EE
authors.lastname: Baird
authors.forename: D E
authors.initials: DE
authors.lastname: Mosier
authors.forename: J M
authors.initials: JM
authors.lastname: Gottesfeld
authors.forename: P B
authors.initials: PB
authors.lastname: Dervan
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D002474:Cell-Free System; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015497:HIV-1 / Q000235:genetics* / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D008214:Lymphocytes; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000494:pharmacology*; D012319:RNA Polymerase II / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D016385:TATA Box; D035181:TATA-Box Binding Protein; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D004268:DNA-Binding Proteins; D008024:Ligands; D009838:Oligodeoxyribonucleotides; D011994:Recombinant Proteins; D035181:TATA-Box Binding Protein; D014157:Transcription Factors; D012319:RNA Polymerase II