Selectivity and Targeting of G-quadruplex Binders Activated by Adaptive Binding and Controlled by Chemical Kinetics
Selectivity and Targeting of G-quadruplex Binders Activated by Adaptive Binding and Controlled by Chemical Kinetics
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自适应结合激活和化学动力学控制的 G-四联体结合剂的选择性和靶向性
DOI：
10.1002/anie.202104624
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Z.-W. Mao
中科院分区：
文献类型：
--
作者：
B.-C. Zhu;J. He;W. Liu;X.-Y. Xia;L.-Y. Liu;B.-B. Liang;H.-G. Yao;B. Liu;L.-N. Ji;Z.-W. Mao
G-四链体（G4）普遍存在于癌基因中，是潜在的抗肿瘤药物靶点。然而，化合物与G4的结合选择性仍然面临挑战。在本文中，我们报告了一种铂（II）络合物（Pt 1），其对G4-DNA的亲和力通过自适应结合和结合动力学控制的选择性来激活。Pt 1/VEGF-G4（启动子G4）的解析结构表明Pt 1通过Cl−解离和VEGF-G4的环重排与VEGF-G4的3′-G-四联体相匹配。结合速率常数由配位键断裂/形成决定，与亲和力完全相关。G4-结合后的选择性速率决定结合步骤，Cl−-解离，比dsDNA.Pt1在活细胞中有效靶向G4，有效抑制VEGF表达，并抑制斑马鱼血管生长高2-3个数量级。我们显示了自适应G4结合激活和动力学控制，为靶向G4或类似生物分子的化合物提供了互补的设计原理。
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 ofPt1/VEGF‐G4 (a promoter G4) shows thatPt1matches 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.Pt1potently 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.