4.8 Article

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

Journal

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 61, Issue 13, Pages -

Publisher

WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202114016

Keywords

Cathepsin B; DNA Breakage; Dipeptide Linker; Oligonucleotide-Drug Conjugates; Solid-Phase Synthesis

Funding

  1. UK BBSRC [BB/S018794/1]
  2. BBSRC [BB/S018794/1] Funding Source: UKRI

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Oligonucleotides containing cleavable linkers are versatile tools for stimulus-responsive and site-specific DNA cleavage, but their previous limitations have restricted their in vivo applications. Inspired by cathepsin B-sensitive dipeptide linkers in ADCs, we have developed phosphoramidites of Val-Ala-02 and Val-Ala-Chalcone for automated synthesis of enzyme-cleavable oligonucleotides. Cathepsin B efficiently digests these linkers, enabling cleavage of oligonucleotides or release of small-molecule payloads. We believe that these dipeptide linker phosphoramidites will expand the clinical applications of therapeutic oligonucleotides.
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.

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