American Chemical Society
cb500100z_si_001.pdf (4.25 MB)

Discovery of Selective Ligands for Telomeric RNA G‑quadruplexes (TERRA) through 19F‑NMR Based Fragment Screening

Download (4.25 MB)
journal contribution
posted on 2014-07-18, 00:00 authored by Miguel Garavís, Blanca López-Méndez, Alvaro Somoza, Julen Oyarzabal, Claudio Dalvit, Alfredo Villasante, Ramón Campos-Olivas, Carlos González
Telomeric repeat-containing RNA (TERRA) is a novel and very attractive antitumoral target. Here, we report the first successful application of 19F-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 19F- and 1H 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.