化学干预端粒G-四链体的药物化学生物学研究进展  

Advances in the medicinal chemistry and chemical biology of chemically interfered telomeric G-quadruplexes

作　　者：蔡炅桁 杨丹颜 黄志纾 陈硕斌 CAI Jiong-heng;YANG Dan-yan;HUANG Zhi-shu;CHEN Shuo-bin(School of Pharmacy,Sun Yat-sen University,Guangzhou 510006,China)

机构地区：[1]中山大学药学院,广东广州510006

出　　处：《中国药物化学杂志》2023年第10期736-751,F0002,共17页Chinese Journal of Medicinal Chemistry

基　　金：国家自然科学基金重点项目(81930098);国家自然科学基金面上项目(81973184);广东省自然科学基金杰出青年项目(2019B151502015)。

摘　　要：端粒是真核生物染色体末端重要的功能性结构,在维持染色体的完整性和调控细胞命运中发挥重要作用。人类端粒DNA由富鸟嘌呤的TTAGGG重复序列组成,该序列可以折叠形成具有四螺旋特征的G-四链体(G4)结构。研究表明,端粒G4结构在端粒的损伤修复等过程中具有重要作用。通过小分子稳定端粒G4结构的折叠状态往往会导致细胞衰老与凋亡,提示G4结构的折叠与去折叠可能是端粒功能动态调控的关键形式之一。发展可特异性作用端粒G4的小分子配体,开展化学干预研究,对解析端粒调控机制、验证端粒作为潜在治疗新靶点的可行性均十分重要。近年来基于化学干预的端粒G4研究领域获得了许多重要进展。本综述将重点介绍以端粒G4为靶点的药物化学与化学生物学研究进展,探讨G4与端粒结构维持之间的联系,综述端粒G4配体的设计思路并介绍其药理学作用特征,以期为基于端粒G4结构的生物学功能解析与药物发现研究提供参考。Telomeres are important functional structures at the ends of eukaryotic chromosomes and play an important role in maintaining the integrity of chromosomes and regulating cell fate.Human telomeric DNA consists of a guanine-rich TTAGGG repeat sequence that folds to form a G-quadruplex(G4)structure with quadruple helix characteristics.Studies have shown that the telomeric G4 structure has an important role in telomere damage repair and other processes.Stabilization of the folded state of telomeric G4 structures by small molecules often leads to cellular senescence and apoptosis,suggesting that the folding and de-folding of G4 structures may be one of the key forms in the dynamic regulation of telomere function.The development of small molecule ligands that can specifically act on telomeric G4 and chemical intervention studies are important for resolving telomere regulatory mechanisms and verifying the feasibility of telomeres as potential new therapeutic targets.In recent years,many important advances have been made in the field of telomeric G4 research based on chemical interventions.This review will focus on the advances in medicinal chemistry and chemical biology targeting telomeric G4,explore the connection between G4 and telomere structure maintenance,and review the design of telomeric G4 ligands and introduce their pharmacological action characteristics,with the aim of providing a reference for telomeric G4 structure-based biological function analysis and drug discovery studies.

关 键 词：端粒 G-四链体 化学探针 先导化合物 

分 类 号：R914[医药卫生—药物化学]