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 . I...
| Main Authors: | , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Wiley
2022
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| _version_ | 1797106863139979264 |
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| author | Jin, C Sagheer, AHE Li, S Vallis, KA Tan, W Brown, T |
| author_facet | Jin, C Sagheer, AHE Li, S Vallis, KA Tan, W Brown, T |
| author_sort | Jin, C |
| collection | OXFORD |
| 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. |
| first_indexed | 2024-03-07T07:08:32Z |
| format | Journal article |
| id | oxford-uuid:f1bcc29c-9be2-4fb8-aa77-520f7e26a5ee |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:08:32Z |
| publishDate | 2022 |
| publisher | Wiley |
| record_format | dspace |
| spelling | oxford-uuid:f1bcc29c-9be2-4fb8-aa77-520f7e26a5ee2022-05-23T08:20:29ZEngineering enzyme-cleavable oligonucleotides by automated solid-phase incorporation of cathepsin B sensitive dipeptide linkersJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:f1bcc29c-9be2-4fb8-aa77-520f7e26a5eeEnglishSymplectic ElementsWiley2022Jin, CSagheer, AHELi, SVallis, KATan, WBrown, TOligonucleotides 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. |
| spellingShingle | Jin, C Sagheer, AHE Li, S Vallis, KA Tan, W Brown, T 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 |
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