Modular and automated synthesis of oligonucleotide-small molecule conjugates for cathepsin B mediated traceless release of payloads † ‡
The reversible attachment of small molecules to oligonucleotides provides versatile tools for the development of improved oligonucleotide therapeutics. However, cleavable linkers in the oligonucleotide field are scarce, particularly with respect to the requirement for traceless release of the payloa...
| Main Authors: | , , , , |
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| Format: | Journal article |
| Language: | English |
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Royal Society of Chemistry
2024
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| _version_ | 1826313813221179392 |
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| author | Jin, C Li, S Vallis, KA El-Sagheer, AH Brown, T |
| author_facet | Jin, C Li, S Vallis, KA El-Sagheer, AH Brown, T |
| author_sort | Jin, C |
| collection | OXFORD |
| description | The reversible attachment of small molecules to oligonucleotides provides versatile tools for the development of improved oligonucleotide therapeutics. However, cleavable linkers in the oligonucleotide field are scarce, particularly with respect to the requirement for traceless release of the payload in vivo. Herein, we describe a cathepsin B-cleavable dipeptide phosphoramidite, Val-Ala(NB) for the automated synthesis of oligonucleotide-small molecule conjugates. Val-Ala(NB) was protected by a photolabile 2-nitrobenzyl group to improve the stability of the peptide linker during DNA synthesis. Intracellular cathepsin B digests the dipeptide efficiently, releasing the payload-phosphate which is converted to the free payload by endogenous phosphatase enzymes. With the advantages of modular synthesis and stimuli-responsive drug release, we believe Val-Ala(NB) will be a potentially valuable cleavable linker for use in oligonucleotide-drug conjugates. |
| first_indexed | 2024-09-25T04:22:28Z |
| format | Journal article |
| id | oxford-uuid:ac07b4cb-bd0e-4635-9e96-ad40c32e58a2 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-09-25T04:22:28Z |
| publishDate | 2024 |
| publisher | Royal Society of Chemistry |
| record_format | dspace |
| spelling | oxford-uuid:ac07b4cb-bd0e-4635-9e96-ad40c32e58a22024-08-10T19:33:44ZModular and automated synthesis of oligonucleotide-small molecule conjugates for cathepsin B mediated traceless release of payloads † ‡Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:ac07b4cb-bd0e-4635-9e96-ad40c32e58a2EnglishJisc Publications RouterRoyal Society of Chemistry2024Jin, CLi, SVallis, KAEl-Sagheer, AHBrown, TThe reversible attachment of small molecules to oligonucleotides provides versatile tools for the development of improved oligonucleotide therapeutics. However, cleavable linkers in the oligonucleotide field are scarce, particularly with respect to the requirement for traceless release of the payload in vivo. Herein, we describe a cathepsin B-cleavable dipeptide phosphoramidite, Val-Ala(NB) for the automated synthesis of oligonucleotide-small molecule conjugates. Val-Ala(NB) was protected by a photolabile 2-nitrobenzyl group to improve the stability of the peptide linker during DNA synthesis. Intracellular cathepsin B digests the dipeptide efficiently, releasing the payload-phosphate which is converted to the free payload by endogenous phosphatase enzymes. With the advantages of modular synthesis and stimuli-responsive drug release, we believe Val-Ala(NB) will be a potentially valuable cleavable linker for use in oligonucleotide-drug conjugates. |
| spellingShingle | Jin, C Li, S Vallis, KA El-Sagheer, AH Brown, T Modular and automated synthesis of oligonucleotide-small molecule conjugates for cathepsin B mediated traceless release of payloads † ‡ |
| title | Modular and automated synthesis of oligonucleotide-small molecule conjugates for cathepsin B mediated traceless release of payloads † ‡ |
| title_full | Modular and automated synthesis of oligonucleotide-small molecule conjugates for cathepsin B mediated traceless release of payloads † ‡ |
| title_fullStr | Modular and automated synthesis of oligonucleotide-small molecule conjugates for cathepsin B mediated traceless release of payloads † ‡ |
| title_full_unstemmed | Modular and automated synthesis of oligonucleotide-small molecule conjugates for cathepsin B mediated traceless release of payloads † ‡ |
| title_short | Modular and automated synthesis of oligonucleotide-small molecule conjugates for cathepsin B mediated traceless release of payloads † ‡ |
| title_sort | modular and automated synthesis of oligonucleotide small molecule conjugates for cathepsin b mediated traceless release of payloads † ‡ |
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