摘要
目的介绍靶向蛋白质降解(TPD)技术中“蛋白水解靶向嵌合体(PROTACs)”技术的作用机制和设计原理,讨论现有基于PROTACs技术药物的潜在风险及解决方案,以期为新型、高效且安全性较高的PROTACs类药物研发提供参考。方法分析近年来已发表的相关文献信息,归纳PROTACs技术的作用机制、各组成部分的设计原理、已发现的潜在风险及已报道的应对策略。结果对PROTACs类药物的设计,多从靶蛋白结合分子的溶剂暴露区域选择合适的位点与连接链结合,同时该设计应基于高分辨率的晶体结构,并且应避免小分子与靶蛋白的结合亲和力发生变化;在E3连接酶及其配体选择上,多是先从使用较为广泛的CRBN和VHL连接酶配体开始进行逐步筛选;在连接链设计上,多是从柔性PEG类链开始筛选;在潜在风险上,PROTACs类药物存在如过度降解、脱靶毒性、Hook效应、代谢产物毒性、醛氧化酶参与代谢、linker断裂型产物毒性等问题。结论建议将PTOTACs化合物视为整体看待,灵活应用蛋白质组学等技术方法,预防与监测分析该类化合物的代谢产物毒性,为开发活性更好、安全性更高的PROT ACs药物奠定基础。
Objective To introduce the mechanism and design principles of protein hydrolysis targeting chimeras(PROTACs)in Targeted Protein Degradation(TPD)technology,and to discuss the potential risks of and solutions to existing PROTACs based drugs in order to provide reference for the development of new,efficient and safe PROTAC drugs.Methods Relevant literature published in recent years was analyzed.The mechanism of PROTACs technology,design principles of each component,identified potential risks,and corresponding response strategies were summarized.Results For the design of PROTAC drugs,suitable sites and connecting chains should be selected from the solvent exposure areas of target protein binding molecules.At the same time,this design should be based on high-resolution crystal structures and avoid changes in the binding affinity between small molecules and target proteins.For the selection of E3 ligases and their ligands,screening usually starts with the widely used CRBN and VHL ligands.In the design of connecting chains,screening often starts from flexible PEG chains.In terms of potential risks,PROTAC drugs can cause such problems as excessive degradation,off target toxicity,Hook effect,metabolite toxicity,involvement of aldehyde oxidase in metabolism,and linker cleavage product toxicity.Conclusion PTOTAC compounds should be viewed as a whole,and proteomics and other technical methods should be flexibly applied to prevent,monitor and analyze the toxicity of their metabolites so as to facilitate the development of more active and safe PROTAC drugs.
作者
姜海伦
周辛波
肖典
钟武
李松
JIANG Hailun;ZHOU Xinbo;XIAO Dian;ZHONG Wu;LI Song(National Engineering Research Center for the Strategic Drug of AMMS,Beijing 100850,China)
出处
《中国药物警戒》
2024年第7期730-734,共5页
Chinese Journal of Pharmacovigilance
基金
国家自然科学基金资助项目(L2324220)。
