title: Fragment based search for small molecule inhibitors of HIV-1 Tat-TAR.
abstract: Basic molecular building blocks such as benzene rings, amidines, guanidines, and amino groups have been combined in a systematic way to generate ligand candidates for HIV-1 TAR RNA. Ranking of the resulting compounds was achieved in a fluorimetric Tat-TAR competition assay. Although simple molecules such as phenylguanidine are inactive, few iteration steps led to a set of ligands with IC50 values ranging from 40 to 150 μM. 1,7-Diaminoisoquinoline 17 and 2,4,6-triaminoquinazoline 22 have been further characterized by NMR titrations with TAR RNA. Compound 22 is bound to TAR at two high affinity sites and shows slow exchange between the free ligand and the RNA complex. These results encourage investigations of dimeric ligands built from two copies of compound 22 or related heterocycles.
authors.affiliation: Goethe-Universität Frankfurt am Main, Institut für Organische und Chemische Biologie, D-60438 Frankfurt am Main, Germany.
authors.forename: Mirco
authors.initials: M
authors.lastname: Zeiger
authors.affiliation: Goethe-Universität Frankfurt am Main, Institut für Organische und Chemische Biologie, D-60438 Frankfurt am Main, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Stark
authors.affiliation: Goethe-Universität Frankfurt am Main, Institut für Organische und Chemische Biologie, D-60438 Frankfurt am Main, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kalden
authors.affiliation: Goethe-Universität Frankfurt am Main, Institut für Organische und Chemische Biologie, D-60438 Frankfurt am Main, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Ackermann
authors.affiliation: Goethe-Universität Frankfurt am Main, Institut für Organische und Chemische Biologie, D-60438 Frankfurt am Main, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Ferner
authors.affiliation: Goethe-Universität Frankfurt am Main, Institut für Organische und Chemische Biologie, D-60438 Frankfurt am Main, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Scheffer
authors.affiliation: Goethe-Universität Frankfurt am Main, Institut für Organische und Chemische Biologie, D-60438 Frankfurt am Main, Germany.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Shoja-Bazargani
authors.affiliation: Goethe-Universität Frankfurt am Main, Institut für Organische und Chemische Biologie, D-60438 Frankfurt am Main, Germany.
authors.forename: Veysel
authors.initials: V
authors.lastname: Erdel
authors.affiliation: Goethe-Universität Frankfurt am Main, Institut für Organische und Chemische Biologie, D-60438 Frankfurt am Main, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Schwalbe
authors.affiliation: Goethe-Universität Frankfurt am Main, Institut für Organische und Chemische Biologie, D-60438 Frankfurt am Main, Germany. Electronic address: M.Goebel@chemie.uni-frankfurt.de.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Göbel
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D001665:Binding Sites; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D009690:Nucleic Acid Conformation; D012367:RNA, Viral / Q000737:chemistry / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D008024:Ligands; D012367:RNA, Viral; D054852:Small Molecule Libraries; D054322:tat Gene Products, Human Immunodeficiency Virus
keywords: Amidine; Guanidine; Ligand; NMR; RNA