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

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• 作者：Miguel Garav铆s ; Blanca L贸pez-M茅ndez ; Alvaro Somoza ; Julen Oyarzabal ; Claudio Dalvit ; Alfredo Villasante ; Ram贸n Campos-Olivas ; Carlos Gonz谩lez
• 刊名：ACS Chemical Biology
• 出版年：2014
• 出版时间：July 18, 2014
• 年：2014
• 卷：9
• 期：7
• 页码：1559-1566
• 全文大小：428K
• ISSN：1554-8937

文摘

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.