Selective RNA Versus DNA G‐Quadruplex Targeting by In Situ Click Chemistry

Abstract

Alles klickt zusammen: Mittels kupferfreier 1,3‐dipolarer Cycloaddition einer Serie von Alkin‐ und Azid‐Bausteinen mit einer nicht‐Watson‐Crick‐artigen DNA‐Sekundärstruktur als Katalysator gelang die Identifizierung einer potenten Telomer‐erkennenden niedermolekularen Verbindung (siehe Bild). Die Methode ist allgemein anwendbar und liefert niedermolekulare Sonden, die selektiv zwischen einer gegebenen RNA oder DNA unterscheiden können.

Solution Structure of a G‐quadruplex Bound to the Bisquinolinium Compound Phen‐DC3

“…This strategy has been developed recently on a Phen‐DC 3 platform46 by the addition of cationic side chains (see Figure S14), which slightly improved the binding but at the expense of selectivity and cell permeation. It might be better to explore the effect of neutral or even anionic functions, as reported recently for pyridostatin 48. The present structure determined by NMR spectroscopy points to the possibility of additional groove‐binding interactions, which could result from a combination of the functionalization of the k and/or k′ position and the extension of the N ‐methyl groups to create a three‐point anchor for a more specific binding of the bisquinolinium compound to the G‐quadruplex.…”

G-quadruplex RNA binding and recognition by the lysine-specific histone demethylase-1 enzyme

“…Although GQ RNA shape-based recognition is not well established, it is known that other protein domains can also preferentially recognize GQ-forming RNAs including: the arginine-glycine-glycine repeat (RGG) domain of Fragile-X mental retardation protein (FMRP), the glycine-argininerich (GAR) domain of TRF2, and the N-terminal domain of the DEAH-box ATP-dependent helicase 36 (DHX36) (Deng et al 2009;Meier et al 2013;Chen et al 2015;Vasilyev et al 2015). With the development of GQ-specific antibodies that have unambiguously identified GQ TERRA RNA structures in living cells (Xu et al 2010;Di Antonio et al 2012;Biffi et al 2013Biffi et al , 2014, more biophysical studies are needed that probe how protein domains and multidomain protein complexes recognize the molecular architecture of GQ RNAs. Our data have defined how TERRA's secondary and tertiary structural motifs can serve as recognition elements for LSD1 interactions by coupling biophysical studies (CD/AUC), EMSA, enzyme kinetics, XL-MS, and X-ray crystallographic methods.…”

Solution Structure of a G‐quadruplex Bound to the Bisquinolinium Compound Phen‐DC3

“…It might be better to explore the effect of neutral or even anionic functions, as reported recently for pyridostatin. [48] The present structure determined by NMR spectroscopy points to the possibility of additional groove-binding interactions, which could result from a combination of the functionalization of the k and/or k' position and the extension of the N-methyl groups to create a three-point anchor for a more specific binding of the bisquinolinium compound to the G-quadruplex.…”