疏水标签靶向蛋白降解剂的应用进展  

Advances in the Application of Hydrophobic Label-targeted Protein Degradation Agents

作　　者：余思琦 王京 王琴 张磊 YU Si-qi;WANG Jing;WANG Qin;ZHANG Lei(School of Pharmacy,Zunyi Medical University,Zunyi 563006,China;Key Laboratory for Modernization of Qiandongnan Miao&Dong Medicine,School of Life and Health Science,Kaili University,Kaili 556011,China)

机构地区：[1]遵义医科大学药学院,贵州遵义563006 [2]凯里学院大健康学院黔东南苗侗药现代化研究重点实验室,贵州凯里556011

出　　处：《化学试剂》2025年第4期33-42,共10页Chemical Reagents

基　　金：黔科合基础项目(ZK(2023)499)。

摘　　要：近年来,靶向蛋白降解技术蓬勃发展,其能够选择性且有效地触发目标蛋白质的降解,有望克服传统药物研发技术的瓶颈问题,挑战“难成药”靶点,为靶向药物领域提供新的治疗策略。这种新颖的方法相比常规小分子抑制剂具有多种优势,如低剂量、高选择性、克服耐药性等优点。靶向蛋白质降解策略包括分子胶、蛋白水解靶向嵌合体和基于疏水标签的降解剂等。与其他的靶向蛋白降解剂相比,疏水标签蛋白降解剂是通过模拟蛋白错误折叠而被蛋白酶体识别并降解,但是具体的降解机制还有待进一步研究。目前不同结构的疏水标签被报道,例如金刚烷、Boc_(3)Arg、降冰片烯、芘、芴、碳硼烷等,而且疏水标签降解剂优异的成药性与可设计性,已广泛应用于多个研究领域。但现有的疏水标签在诸多方面存在的问题,仍存在理化性质差、易被消除、生物利用度较低、降解效率不高等缺点,对疏水标签降解剂的发展形成了一定阻碍。因此主要介绍了近年来疏水标签降解剂在药物研发领域中的应用进展,希望为未来靶向蛋白降解剂的研发提供有价值的参考。In recent years,targeted protein degradation technology has developed vigorously,which can selectively and effectively trigger the degradation of target proteins.It is expected to overcome the bottleneck of traditional drug development technology,challenge“undruggable”targets,and provide new therapeutic strategies for the field of targeted drugs.This novel approach has several advantages over conventional small molecule inhibitors,such as low dose,high selectivity,and overcoming drug resistance.Targeted protein degradation strategies include molecular glues,proteolytic targeting chimeras,and hydrophobic tag degraders.Compared with other targeted protein degraders,hydrophobic tag protein degraders are recognized and degraded by the proteasome by mimicking protein misfolding,but the specific degradation mechanism needs to be further studied.At present,hydrophobic tags with different structures have been reported,such as adamantane,Boc_(3)Arg,norbornene,pyrene,fluorene,carborane,etc.Among them,hydrophobic tag has various applications due to its druggability and designability compared with other targeted protein degradation molecules.However,the existing hydrophobic labels still have the shortcomings of poor physical and chemical properties,easy elimination,low bioavailability,and low degradation efficiency,which hinder the development of hydrophobic label degraders.The recent applications of hydrophobic tag degraders in drug development were highlighted,which might provide valuable information for the future research and development of targeted protein degraders.

关 键 词：疏水标签 靶向蛋白降解 靶向药物 药物研发 蛋白酶 

分 类 号：O66[理学—分析化学]