biostudies-literatureLiczner CNatural Sciences and Engineering Research Council of CanadaFonds de recherche du Québec – Nature et technologies410-420https://www.ebi.ac.uk/biostudies/studies/S-EPMC8729807biostudies-literatureUnknown13(2)A breadth of strategies are needed to efficiently modify oligonucleotides with peptides or lipids to capitalize on their therapeutic and diagnostic potential, including the modulation of <i>in vivo</i> chemical stability and for applications in cell-targeting and cell-permeability. The chemical linkages typically used in peptide oligonucleotide conjugates (POCs) have limitations in terms of stability and/or ease of synthesis. Herein, we report an efficient method for POC synthesis using a diselenide-selenoester ligation (DSL)-deselenization strategy that rapidly generates a stable amide linkage between the two biomolecules. This conjugation strategy is underpinned by a novel selenide phosphoramidite building block that can be incorporated into an oligonucleotide by solid-phase synthesis toChemical scienceGeneration of oligonucleotide conjugates <i>via</i> one-pot diselenide-selenoester ligation-deselenization/alkylation.PMC8729807RGPIN-2017-06683Liczner CHanna CCPayne RJWilds CJfalseGeneration of oligonucleotide conjugates <i>via</i> one-pot diselenide-selenoester ligation-deselenization/alkylation.A breadth of strategies are needed to efficiently modify oligonucleotides with peptides or lipids to capitalize on their therapeutic and diagnostic potential, including the modulation of <i>in vivo</i> chemical stability and for applications in cell-targeting and cell-permeability. The chemical linkages typically used in peptide oligonucleotide conjugates (POCs) have limitations in terms of stability and/or ease of synthesis. Herein, we report an efficient method for POC synthesis using a diselenide-selenoester ligation (DSL)-deselenization strategy that rapidly generates a stable amide linkage between the two biomolecules. This conjugation strategy is underpinned by a novel selenide phosphoramidite building block that can be incorporated into an oligonucleotide by solid-phase synthesis to2022-01-01T00:00:00Z2022 Jan2025-04-22T08:31:42.492Z2025-04-05T22:33:39.597ZS-EPMC87298073512697310.1039/d1sc04937b