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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 of previously reported cleavable linkers including photolabile and disulfide linkers have restricted their applications in vivo. In...

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Autores principales: Jin, Cheng, EI‐Sagheer, Afaf H., Li, Siqi, Vallis, Katherine A., Tan, Weihong, Brown, Tom
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9306542/
https://www.ncbi.nlm.nih.gov/pubmed/34953094
http://dx.doi.org/10.1002/anie.202114016
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author Jin, Cheng
EI‐Sagheer, Afaf H.
Li, Siqi
Vallis, Katherine A.
Tan, Weihong
Brown, Tom
author_facet Jin, Cheng
EI‐Sagheer, Afaf H.
Li, Siqi
Vallis, Katherine A.
Tan, Weihong
Brown, Tom
author_sort Jin, Cheng
collection PubMed
description 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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spelling pubmed-93065422022-07-28 Engineering Enzyme‐Cleavable Oligonucleotides by Automated Solid‐Phase Incorporation of Cathepsin B Sensitive Dipeptide Linkers Jin, Cheng EI‐Sagheer, Afaf H. Li, Siqi Vallis, Katherine A. Tan, Weihong Brown, Tom Angew Chem Int Ed Engl Research Articles 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. John Wiley and Sons Inc. 2022-02-10 2022-03-21 /pmc/articles/PMC9306542/ /pubmed/34953094 http://dx.doi.org/10.1002/anie.202114016 Text en © 2021 The Authors. Published by Wiley-VCH GmbH https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Jin, Cheng
EI‐Sagheer, Afaf H.
Li, Siqi
Vallis, Katherine A.
Tan, Weihong
Brown, Tom
Engineering Enzyme‐Cleavable Oligonucleotides by Automated Solid‐Phase Incorporation of Cathepsin B Sensitive Dipeptide Linkers
title Engineering Enzyme‐Cleavable Oligonucleotides by Automated Solid‐Phase Incorporation of Cathepsin B Sensitive Dipeptide Linkers
title_full Engineering Enzyme‐Cleavable Oligonucleotides by Automated Solid‐Phase Incorporation of Cathepsin B Sensitive Dipeptide Linkers
title_fullStr Engineering Enzyme‐Cleavable Oligonucleotides by Automated Solid‐Phase Incorporation of Cathepsin B Sensitive Dipeptide Linkers
title_full_unstemmed Engineering Enzyme‐Cleavable Oligonucleotides by Automated Solid‐Phase Incorporation of Cathepsin B Sensitive Dipeptide Linkers
title_short Engineering Enzyme‐Cleavable Oligonucleotides by Automated Solid‐Phase Incorporation of Cathepsin B Sensitive Dipeptide Linkers
title_sort engineering enzyme‐cleavable oligonucleotides by automated solid‐phase incorporation of cathepsin b sensitive dipeptide linkers
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9306542/
https://www.ncbi.nlm.nih.gov/pubmed/34953094
http://dx.doi.org/10.1002/anie.202114016
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