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Improved Metal-Free Approach for the Synthesis of Protected Thiol Containing Thymidine Nucleoside Phosphoramidite and Its Application for the Synthesis of Ligatable Oligonucleotide Conjugates

Kupihár, Zoltán and Ferenc, Györgyi and Petrovicz, Vencel L. and Fáy, Viktória R. and Kovács, Lajos and Martinek, Tamás and Hegedüs, Zsófia (2023) 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, 15 (1). No-248. ISSN 1999-4923

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Abstract

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.

Item Type: Article
Additional Information: Funding Agency and Grant Number: National Research, Development and Innovation Office of Hungary [NKFIH PD 135324, K 128801, K 134754]; Ministry of Innovation and Technology of Hungary through the National Research, Development and Innovation Fund [TKP2021-EGA-32] Funding text: This work received funding from the National Research, Development and Innovation Office of Hungary-NKFIH PD 135324 (Z.H.), K 128801 (L.K.) and K 134754 (T.A.M.). Support by the Ministry of Innovation and Technology of Hungary through the National Research, Development and Innovation Fund (TKP2021-EGA-32) is acknowledged.
Uncontrolled Keywords: nucleoside synthesis; oligonucleotide conjugates; ligatable oligonucleotides; solid-phase conjugation; thiol-maleimide conjugation; templated ligation
Subjects: Q Science / természettudomány > QD Chemistry / kémia > QD04 Organic chemistry / szerves kémia
R Medicine / orvostudomány > R1 Medicine (General) / orvostudomány általában
SWORD Depositor: MTMT SWORD
Depositing User: MTMT SWORD
Date Deposited: 26 Sep 2023 10:05
Last Modified: 26 Sep 2023 10:05
URI: http://real.mtak.hu/id/eprint/174986

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