Discovery of selective ligands for telomeric RNA G-quadruplexes (TERRA) through 19F-NMR based fragment screening.
Telomeric repeat-containing RNA (TERRA) is a novel and very attractive antitumoral target. Here, we report the first successful application of (19)F-NMR fragment-based screening to identify chemically diverse compounds that bind to an RNA molecule such as TERRA. We have built a library of 355 fluorinated fragments, and checked their interaction with a long telomeric RNA as a target molecule. The screening resulted in the identification of 20 hits (hit rate of 5.6%). For a number of binders, their interaction with TERRA was confirmed by (19)F- and (1)H NMR as well as by CD melting experiments. We have also explored the selectivity of the ligands for RNA G-quadruplexes and found that some of the hits do not interact with other nucleic acids such as tRNA and duplex DNA and, most importantly, favor the propeller-like parallel conformation in telomeric DNA G-quadruplexes. This suggests a selective recognition of this particular quadruplex topology and that different ligands may recognize specific sites in propeller-like parallel G-quadruplexes. Such features make some of the resulting binders promising lead compounds for fragment based drug discovery.
Instituto de Química Física 'Rocasolano' , CSIC, Serrano 119, 28006 Madrid, Spain.
Miguel
M
Garavís
Blanca
B
López-Méndez
Alvaro
A
Somoza
Julen
J
Oyarzabal
Claudio
C
Dalvit
Alfredo
A
Villasante
Ramón
R
Campos-Olivas
Carlos
C
González
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001483:Base Sequence; D055808:Drug Discovery; D054856:G-Quadruplexes / Q000187:drug effects*; D054879:Halogenation; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy; D019906:Nuclear Magnetic Resonance, Biomolecular; D012313:RNA / Q000737:chemistry / Q000378:metabolism*; D012091:Repetitive Sequences, Nucleic Acid / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology; D016615:Telomere / Q000737:chemistry / Q000378:metabolism
D000970:Antineoplastic Agents; D008024:Ligands; D054852:Small Molecule Libraries; D012313:RNA