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Selectivity and Targeting of G‐Quadruplex Binders Activated by Adaptive Binding and Controlled by Chemical Kinetics
Author(s) -
Zhu BoChen,
He Juan,
Liu Wenting,
Xia XiaoYu,
Liu LiuYi,
Liang BingBing,
Yao HuaGang,
Liu Bing,
Ji LiangNian,
Mao ZongWan
Publication year - 2021
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202104624
Subject(s) - chemistry , selectivity , kinetics , g quadruplex , receptor–ligand kinetics , dissociation rate , affinities , binding selectivity , biophysics , binding site , stereochemistry , dissociation constant , dna , dissociation (chemistry) , combinatorial chemistry , biochemistry , receptor , biology , catalysis , physics , quantum mechanics
G‐quadruplexes (G4s) are prevalent in oncogenes and are potential antitumor drug targets. However, binding selectivity of compounds to G4s still faces challenges. Herein, we report a platinum(II) complex ( Pt1 ), whose affinity to G4‐DNA is activated by adaptive binding and selectivity controlled by binding kinetics. The resolved structure of Pt1 /VEGF‐G4 (a promoter G4) shows that Pt1 matches 3′‐G‐tetrad of VEGF‐G4 through Cl − ‐dissociation and loop rearrangement of VEGF‐G4. Binding rate constants are determined by coordination bond breakage/formation, correlating fully with affinities. The selective rate‐determining binding step, Cl − ‐dissociation upon G4‐binding, is 2–3 orders of magnitude higher than dsDNA. Pt1 potently targets G4 in living cells, effectively represses VEGF expression, and inhibits vascular growth in zebrafish. We show adaptive G4‐binding activation and controlled by kinetics, providing a complementary design principle for compounds targeting G4 or similar biomolecules.