Adaptive and Specific Recognition of Telomeric G-Quadruplexes via Polyvalency Induced Unstacking of Binding Units

Journal of the American Chemical Society
Jibin Abraham PunnooseHanbin Mao

Abstract

Targeting DNA G-quadruplexes using small-molecule ligands has shown to modulate biological functions mediated by G-quadruplexes inside cells. Given >716 000 G-quadruplex hosting sites in human genome, the specific binding of ligands to quadruplex becomes problematic. Here, we innovated a polyvalency based mechanism to specifically target multiple telomeric G-quadruplexes. We synthesized a tetrameric telomestatin derivative and evaluated its complex polyvalent binding with multiple G-quadruplexes by single-molecule mechanical unfolding in laser tweezers. We found telomestatin tetramer binds to multimeric telomeric G-quadruplexes >40 times stronger than monomeric quadruplexes, which can be ascribed to the polyvalency induced unstacking of binding units (or PIU binding) for G-quadruplexes. While stacking of telomestatin units in the tetramer imparts steric hindrance for the ligand to access stand-alone G-quadruplexes, the stacking disassembles to accommodate the potent polyvalent binding between the tetramer ligand and multimeric G-quadruplexes. We anticipate this adaptive PIU binding offers a generic mechanism to selectively target polymeric biomolecules prevalent inside cells.

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Citations

Feb 24, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Tong CheShuo-Bin Chen
Dec 12, 2017·Chembiochem : a European Journal of Chemical Biology·Andrea FunkeKlaus Weisz
Jul 28, 2018·Chemistry : a European Journal·Sefan AsamitsuHiroshi Sugiyama
Jan 3, 2019·Angewandte Chemie·Manish DebnathJyotirmayee Dash
Jan 27, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Sefan AsamitsuHiroshi Sugiyama
Nov 28, 2017·Organic & Biomolecular Chemistry·Zi-Qi LiChun-Qiong Zhou
Jan 16, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Yue MaKazuo Nagasawa
May 10, 2019·Chemistry : a European Journal·Ryusuke TakeuchiShigeori Takenaka

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