Engineering Enzyme-Cleavable Oligonucleotides by Automated Solid-Phase Incorporation of Cathepsin B Sensitive Dipeptide Linkers

Cheng Jin, A. H. EI-Sagheer, Siqi Li, Katherine A. Vallis, Weihong Tan, Tom Brown. Angew. Chem. Int. Ed. e202114016 1, 2022.


Cathepsin B-sensitive dipeptide phosphoramidites were developed for automated synthesis of enzyme-cleavable oligonucleotides. The enzymatic cleavage of Val-Ala-02 by cathepsin B is efficient in the context of single-stranded DNA, but is sterically hindered by double-stranded DNA and short hairpin loops. The design of Val-Ala-Chalcone allows the construction of oligonucleotide–drug conjugates which release their small-molecule payload after enzymatic cleavage.