Jin Cheng, Ei-Sagheer Afaf H, Li Siqi, Vallis Katherine A, Tan Weihong, Brown Tom
Department of Chemistry, Chemistry Research Laboratory University of Oxford 12 Mansfield Road Oxford OX1 3TA UK.
Department of Science and Mathematics Suez University, Faculty of Petroleum and Mining Engineering Suez 43721 Egypt.
Angew Chem Weinheim Bergstr Ger. 2022 Mar 21;134(13):e202114016. doi: 10.1002/ange.202114016. Epub 2022 Feb 10.
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.
含有可裂解连接子的寡核苷酸已成为实现DNA刺激响应性和位点特异性裂解的通用工具。然而，先前报道的可裂解连接子（包括光不稳定连接子和二硫键连接子）的局限性限制了它们在体内的应用。受诸如Adcetris等抗体药物偶联物（ADC）中组织蛋白酶B敏感二肽连接子的启发，我们开发了用于自动合成酶可裂解寡核苷酸的缬氨酸-丙氨酸-02和缬氨酸-丙氨酸-查耳酮亚磷酰胺。组织蛋白酶B能有效消化缬氨酸-丙氨酸-02和缬氨酸-丙氨酸-查耳酮连接子，使寡核苷酸裂解为两个组分或释放小分子载荷。基于二肽连接子在ADC中的先前成功，我们相信这些二肽连接子亚磷酰胺将促进治疗性寡核苷酸的新临床应用。
