title: Specific binding of a hexanucleotide to HIV-1 reverse transcriptase: a novel class of bioactive molecules.
abstract: Short oligonucleotides below 8-10 nt in length adopt relatively simple structures. Accordingly, they represent interesting and so far unexplored lead compounds as molecular tools and, potentially, for drug development as a rational improvement of efficacy seem to be less complex than for other classes of longer oligomeric nucleic acid. As a 'proof of concept', we describe the highly specific binding of the hexanucleotide UCGUGU (Hex-S3) to human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) as a model target. Ultraviolet (UV) cross-linking studies and competition experiments with primer/template substrates and a RT-directed aptamer suggest site-specific binding of Hex-S3 to the large subunit (p66) of the viral enzyme. The affinity of 5.3 muM is related to hexanucleotide-specific suppression of HIV-1 replication in human cells by up to three orders of magnitude indicating that Hex-S3 exerts specific and biologically relevant activity. Experimental evidence described here further suggests a systematic hexamer array-based search for new tools for molecular biology and novel lead compounds in nucleic acid-based drug development.
authors.affiliation: Kompetenzzentrum Drug Design and Target Monitoring, Maria-Göppert-Strasse 1, D-23538 Lübeck, Germany.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mescalchin
authors.forename: Winfried
authors.initials: W
authors.lastname: Wünsche
authors.forename: Sandra D
authors.initials: SD
authors.lastname: Laufer
authors.forename: Dina
authors.initials: D
authors.lastname: Grohmann
authors.forename: Tobias
authors.initials: T
authors.lastname: Restle
authors.forename: Georg
authors.initials: G
authors.lastname: Sczakiel
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry*; D001665:Binding Sites; D002460:Cell Line; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D020411:Oligonucleotide Array Sequence Analysis; D009843:Oligoribonucleotides / Q000737:chemistry*; D014162:Transfection; D014779:Virus Replication
chemical_list: D019380:Anti-HIV Agents; D004791:Enzyme Inhibitors; C515575:Hex-S3 oligonucleotide; D009838:Oligodeoxyribonucleotides; D009843:Oligoribonucleotides; D054303:HIV Reverse Transcriptase