Engineering Enzyme-Cleavable Oligonucleotides by Automated Solid-Phase Incorporation of Cathepsin B Sensitive Dipeptide Linkers.
Engineering Enzyme-Cleavable Oligonucleotides by Automated Solid-Phase Incorporation of Cathepsin B Sensitive Dipeptide Linkers.
复制标题
通过组织蛋白酶 B 敏感二肽接头的自动固相掺入工程酶可切割的寡核苷酸。
DOI：
10.1002/ange.202114016
复制
发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Jin C
中科院分区：
文献类型：
--
作者：
Jin C
含有可切割接头的寡核苷酸已成为实现DNA的刺激响应性和位点特异性切割的通用工具。然而，以前报道的可切割的接头，包括光不稳定和二硫化物接头的局限性，限制了它们在体内的应用。受Adcetris等抗体-药物偶联物（ADC）中的组织蛋白酶B-敏感性二肽接头的启发，我们开发了瓦尔-Ala-02和瓦尔-Ala-查耳酮亚磷酰胺，用于酶可裂解寡核苷酸的自动化合成。组织蛋白酶B有效地使瓦尔-Ala-02和瓦尔-Ala-查耳酮接头断裂，从而能够将寡核苷酸切割成两种组分或释放小分子有效载荷。基于之前二肽连接体在ADC中的成功，我们相信这些二肽连接体亚磷酰胺将促进治疗性寡核苷酸的新临床应用。
Oligonucleotides containing cleavable linkers have emerged as versatile tools to achieve stimulus‐responsive and site‐specific cleavage of DNA. However, the limitations of previously reported cleavable linkers including photolabile and disulfide linkers have restricted their applications in vivo. Inspired by the cathepsin B‐sensitive dipeptide linkers in antibody–drug conjugates (ADCs) such as Adcetris, we have developed Val‐Ala‐02 and Val‐Ala‐Chalcone phosphoramidites for the automated synthesis of enzyme‐cleavable oligonucleotides. Cathepsin B digests Val‐Ala‐02 and Val‐Ala‐Chalcone linkers efficiently, enabling cleavage of oligonucleotides into two components or release of small‐molecule payloads. Based on the prior success of dipeptide linkers in ADCs, we believe that these dipeptide linker phosphoramidites will promote new clinical applications of therapeutic oligonucleotides.