Research output: Contribution to journal › Article › peer-review
Convenient Solid-Phase Attachment of Small-Molecule Ligands to Oligonucleotides via a Biodegradable Acid-Labile P-N-Bond. / Kropacheva, Nadezhda O; Golyshkin, Arseniy A; Vorobyeva, Mariya A et al.
In: Molecules (Basel, Switzerland), Vol. 28, No. 4, 1904, 16.02.2023.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Convenient Solid-Phase Attachment of Small-Molecule Ligands to Oligonucleotides via a Biodegradable Acid-Labile P-N-Bond
AU - Kropacheva, Nadezhda O
AU - Golyshkin, Arseniy A
AU - Vorobyeva, Mariya A
AU - Meschaninova, Mariya I
N1 - Funding: This research was funded by Russian Scientific Foundation: 19-14-00251.
PY - 2023/2/16
Y1 - 2023/2/16
N2 - One of the key problems in the design of therapeutic and diagnostic oligonucleotides is the attachment of small-molecule ligands for targeted deliveries in such a manner that provides the controlled release of the oligonucleotide at a certain moment. Here, we propose a novel, convenient approach for attaching ligands to the 5'-end of the oligonucleotide via biodegradable, acid-labile phosphoramide linkage. The method includes the activation of the 5'-terminal phosphate of the fully protected, support-bound oligonucleotide, followed by interaction with a ligand bearing the primary amino group. This technique is simple to perform, allows for forcing the reaction to completion by adding excess soluble reactant, eliminates the problem of the limited solubility of reagents, and affords the possibility of using different solvents, including water/organic media. We demonstrated the advantages of this approach by synthesizing and characterizing a wide variety of oligonucleotide 5'-conjugates with different ligands, such as cholesterol, aliphatic oleylamine, and p-anisic acid. The developed method suits different types of oligonucleotides (deoxyribo-, 2'-O-methylribo-, ribo-, and others).
AB - One of the key problems in the design of therapeutic and diagnostic oligonucleotides is the attachment of small-molecule ligands for targeted deliveries in such a manner that provides the controlled release of the oligonucleotide at a certain moment. Here, we propose a novel, convenient approach for attaching ligands to the 5'-end of the oligonucleotide via biodegradable, acid-labile phosphoramide linkage. The method includes the activation of the 5'-terminal phosphate of the fully protected, support-bound oligonucleotide, followed by interaction with a ligand bearing the primary amino group. This technique is simple to perform, allows for forcing the reaction to completion by adding excess soluble reactant, eliminates the problem of the limited solubility of reagents, and affords the possibility of using different solvents, including water/organic media. We demonstrated the advantages of this approach by synthesizing and characterizing a wide variety of oligonucleotide 5'-conjugates with different ligands, such as cholesterol, aliphatic oleylamine, and p-anisic acid. The developed method suits different types of oligonucleotides (deoxyribo-, 2'-O-methylribo-, ribo-, and others).
KW - 5′-functionalization
KW - conjugates of oligonucleotides
KW - pH-sensitive phosphoramidate linkage
KW - siRNA
KW - small molecules
KW - solid-phase synthesis
UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85149054301&origin=inward&txGid=ce3f3c4828c866512a020ef7df71af80
UR - https://www.mendeley.com/catalogue/f7a542c6-c7cb-397d-ac69-628185df47e5/
U2 - 10.3390/molecules28041904
DO - 10.3390/molecules28041904
M3 - Article
C2 - 36838892
VL - 28
JO - Molecules
JF - Molecules
SN - 1420-3049
IS - 4
M1 - 1904
ER -
ID: 44521550