posted on 2014-07-18, 00:00authored byMiguel 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.