Synthesis of Oligonucleotide Conjugates Employing a Diselenide Linker

In this study, we report the synthesis of an alkylene linker containing a terminal 2-cyanoethyl protected selenium functionality for coupling at the 5'-end of an oligonucleotide by solid phase synthesis for the preparation of oligonucleotide conjugates. Upon deprotection and cleavage from the solid support, quantitative formation of a 5'-diselenide cross-linked oligonucleotide dimer occurred, which was verified by denaturing polyacrylamide gel electrophoresis, ion-exchange (IEX) high performance liquid chromatography and mass spectrometry. Using dithiothreitol a reducing agent, the diselenide linkage can be converted into the corresponding monomeric selenol, which then reacts with an alkyl halide to form the desired conjugate. The efficient conjugation of various moieties demonstrates the adaptability of the platform to support oligonucleotide-based applications in chemical biology.