Improved Metal-Free Approach for the Synthesis of Protected Thiol Containing Thymidine Nucleoside Phosphoramidite and Its Application for the Synthesis of Ligatable Oligonucleotide Conjugates
Oligonucleotide conjugates are versatile scaffolds that can be applied in DNA-based screening platforms and ligand display or as therapeutics. Several different chemical approaches are available for functionalizing oligonucleotides, which are often carried out on the 5′ or 3′ end. Modifying oligonuc...
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MDPI AG
2023-01-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/15/1/248 |
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| author | Zoltán Kupihár Györgyi Ferenc Vencel L. Petrovicz Viktória R. Fáy Lajos Kovács Tamás A. Martinek Zsófia Hegedüs |
| author_facet | Zoltán Kupihár Györgyi Ferenc Vencel L. Petrovicz Viktória R. Fáy Lajos Kovács Tamás A. Martinek Zsófia Hegedüs |
| author_sort | Zoltán Kupihár |
| collection | DOAJ |
| description | Oligonucleotide conjugates are versatile scaffolds that can be applied in DNA-based screening platforms and ligand display or as therapeutics. Several different chemical approaches are available for functionalizing oligonucleotides, which are often carried out on the 5′ or 3′ end. Modifying oligonucleotides in the middle of the sequence opens the possibility to ligate the conjugates and create DNA strands bearing multiple different ligands. Our goal was to establish a complete workflow that can be applied for such purposes from monomer synthesis to templated ligation. To achieve this, a monomer is required with an orthogonal functional group that can be incorporated internally into the oligonucleotide sequence. This is followed by conjugation with different molecules and ligation with the help of a complementary template. Here, we show the synthesis and the application of a thiol-modified thymidine nucleoside phosphoramidite to prepare ligatable oligonucleotide conjugates. The conjugations were performed both in solution and on solid phase, resulting in conjugates that can be assembled into multivalent oligonucleotides decorated with tissue-targeting peptides using templated ligation. |
| first_indexed | 2024-03-09T11:27:59Z |
| format | Article |
| id | doaj.art-df87164685c1447a87d29b9bdf6619e7 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T11:27:59Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-df87164685c1447a87d29b9bdf6619e72023-11-30T23:59:45ZengMDPI AGPharmaceutics1999-49232023-01-0115124810.3390/pharmaceutics15010248Improved Metal-Free Approach for the Synthesis of Protected Thiol Containing Thymidine Nucleoside Phosphoramidite and Its Application for the Synthesis of Ligatable Oligonucleotide ConjugatesZoltán Kupihár0Györgyi Ferenc1Vencel L. Petrovicz2Viktória R. Fáy3Lajos Kovács4Tamás A. Martinek5Zsófia Hegedüs6Department of Medical Chemistry, University of Szeged, Dom ter 8., H-6720 Szeged, HungaryInstitute of Plant Biology, Biological Research Centre, Eötvös Lóránd Research Network, H-6726 Szeged, HungaryDepartment of Medical Chemistry, University of Szeged, Dom ter 8., H-6720 Szeged, HungaryDepartment of Medical Chemistry, University of Szeged, Dom ter 8., H-6720 Szeged, HungaryDepartment of Medical Chemistry, University of Szeged, Dom ter 8., H-6720 Szeged, HungaryDepartment of Medical Chemistry, University of Szeged, Dom ter 8., H-6720 Szeged, HungaryDepartment of Medical Chemistry, University of Szeged, Dom ter 8., H-6720 Szeged, HungaryOligonucleotide conjugates are versatile scaffolds that can be applied in DNA-based screening platforms and ligand display or as therapeutics. Several different chemical approaches are available for functionalizing oligonucleotides, which are often carried out on the 5′ or 3′ end. Modifying oligonucleotides in the middle of the sequence opens the possibility to ligate the conjugates and create DNA strands bearing multiple different ligands. Our goal was to establish a complete workflow that can be applied for such purposes from monomer synthesis to templated ligation. To achieve this, a monomer is required with an orthogonal functional group that can be incorporated internally into the oligonucleotide sequence. This is followed by conjugation with different molecules and ligation with the help of a complementary template. Here, we show the synthesis and the application of a thiol-modified thymidine nucleoside phosphoramidite to prepare ligatable oligonucleotide conjugates. The conjugations were performed both in solution and on solid phase, resulting in conjugates that can be assembled into multivalent oligonucleotides decorated with tissue-targeting peptides using templated ligation.https://www.mdpi.com/1999-4923/15/1/248nucleoside synthesisoligonucleotide conjugatesligatable oligonucleotidessolid-phase conjugationthiol-maleimide conjugationtemplated ligation |
| spellingShingle | Zoltán Kupihár Györgyi Ferenc Vencel L. Petrovicz Viktória R. Fáy Lajos Kovács Tamás A. Martinek Zsófia Hegedüs Improved Metal-Free Approach for the Synthesis of Protected Thiol Containing Thymidine Nucleoside Phosphoramidite and Its Application for the Synthesis of Ligatable Oligonucleotide Conjugates Pharmaceutics nucleoside synthesis oligonucleotide conjugates ligatable oligonucleotides solid-phase conjugation thiol-maleimide conjugation templated ligation |
| title | Improved Metal-Free Approach for the Synthesis of Protected Thiol Containing Thymidine Nucleoside Phosphoramidite and Its Application for the Synthesis of Ligatable Oligonucleotide Conjugates |
| title_full | Improved Metal-Free Approach for the Synthesis of Protected Thiol Containing Thymidine Nucleoside Phosphoramidite and Its Application for the Synthesis of Ligatable Oligonucleotide Conjugates |
| title_fullStr | Improved Metal-Free Approach for the Synthesis of Protected Thiol Containing Thymidine Nucleoside Phosphoramidite and Its Application for the Synthesis of Ligatable Oligonucleotide Conjugates |
| title_full_unstemmed | Improved Metal-Free Approach for the Synthesis of Protected Thiol Containing Thymidine Nucleoside Phosphoramidite and Its Application for the Synthesis of Ligatable Oligonucleotide Conjugates |
| title_short | Improved Metal-Free Approach for the Synthesis of Protected Thiol Containing Thymidine Nucleoside Phosphoramidite and Its Application for the Synthesis of Ligatable Oligonucleotide Conjugates |
| title_sort | improved metal free approach for the synthesis of protected thiol containing thymidine nucleoside phosphoramidite and its application for the synthesis of ligatable oligonucleotide conjugates |
| topic | nucleoside synthesis oligonucleotide conjugates ligatable oligonucleotides solid-phase conjugation thiol-maleimide conjugation templated ligation |
| url | https://www.mdpi.com/1999-4923/15/1/248 |
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