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 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 fluorina...

Full description

Saved in:
Bibliographic Details
Published in:ACS chemical biology 2014-07, Vol.9 (7), p.1559-1566
Main Authors: Garavís, Miguel, López-Méndez, Blanca, Somoza, Alvaro, Oyarzabal, Julen, Dalvit, Claudio, Villasante, Alfredo, Campos-Olivas, Ramón, González, Carlos
Format: Article
Language:English
Subjects:
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Base Sequence
Drug Discovery
G-Quadruplexes - drug effects
Halogenation
Humans
Ligands
Models, Molecular
Neoplasms - drug therapy
Nuclear Magnetic Resonance, Biomolecular
Repetitive Sequences, Nucleic Acid - drug effects
RNA - chemistry
RNA - metabolism
Small Molecule Libraries - chemistry
Small Molecule Libraries - pharmacology
Telomere - chemistry
Telomere - metabolism
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:1554-8929
1554-8937
DOI:10.1021/cb500100z