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

Oligonucleotides containing cleavable linkers have emerged as versatile tools to achieve stimulus-responsive and site-specific cleavage of DNA. However, the limitations previously reported including photolabile disulfide restricted their applications in vivo. Inspired by cathepsin B-sensitive dipeptide antibody–drug conjugates (ADCs) such Adcetris, we developed Val-Ala-02 Val-Ala-Chalcone phosphoramidites for automated synthesis enzyme-cleavable oligonucleotides. Cathepsin B digests efficiently, enabling oligonucleotides into two components or release small-molecule payloads. Based on prior success ADCs, believe that these linker will promote new clinical therapeutic