核酸G-四联体（G4）已成为癌症和神经退行性疾病等多种疾病的一个有希望的治疗靶点。在小分子G4结合物中，pyridostatin（PDS）及其衍生物（如PyPDS）对G4s具有高度特异性，但其特异性识别G4s的结构基础尚不清楚。
该文中，研究人员提出了PyPDS和具有四重-双工混合的PDS的两种分解结构。结构表明，通过柔性酰胺键连接的PyPDS/PDS的刚性芳香环与G-四分体平面自适应匹配，增强了π–π堆积，实现了对G4s的特异识别。PyPDS/PDS的脂肪胺侧链通过氢键和静电相互作用调整构象以与磷酸盐主链相互作用，增加对G4s的亲和力。此外，PyPDS/PDS酰胺键的N–H通过氢键与G-四分体鸟嘌呤的两个O6s相互作用，进一步提高对G4s的亲和力，这与大多数G4配体不同。
研究结果从结构角度揭示，配体中刚性和柔性结构单元的合理组装可以通过空间选择性和适应性匹配协同提高对G4s的选择性和亲和力。
附：英文原文
Title: Structural Basis of Pyridostatin and Its Derivatives Specifically Binding to G-Quadruplexes
Author: Liu-Yi Liu, Tian-Zhu Ma, You-Liang Zeng, Wenting Liu, Zong-Wan Mao
Issue&Volume: June 24, 2022
Abstract: The nucleic acid G-quadruplex (G4) has emerged as a promising therapeutic target for a variety of diseases such as cancer and neurodegenerative disease. Among small-molecule G4-binders, pyridostatin (PDS) and its derivatives (e.g., PyPDS) exhibit high specificity to G4s, but the structural basis for their specific recognition of G4s remains unknown. Here, we presented two solution structures of PyPDS and PDS with a quadruplex–duplex hybrid. The structures indicate that the rigid aromatic rings of PyPDS/PDS linked by flexible amide bonds match adaptively with G-tetrad planes, enhancing π–π stacking and achieving specific recognition of G4s. The aliphatic amine side chains of PyPDS/PDS adjust conformation to interact with the phosphate backbone via hydrogen bonding and electrostatic interactions, increasing affinity for G4s. Moreover, the N–H of PyPDS/PDS amide bonds interacts with two O6s of G-tetrad guanines via hydrogen bonding, achieving a further increase in affinity for G4s, which is different from most G4 ligands. Our findings reveal from structural perspectives that the rational assembly of rigid and flexible structural units in a ligand can synergistically improve the selectivity and affinity for G4s through spatial selective and adaptive matching.
DOI: 10.1021/jacs.2c04775
Source: https://pubs.acs.org/doi/10.1021/jacs.2c04775
