Harnessing a Universal Solid Support for Automated Amino-Modified Oligonucleotide Synthesis

Résumé fourni par la source

Amino-functionalized nucleic acids constitute a fundamental class of chemical handles with widespread utility in chemical biology, biotechnology, and studies of the origins of life. Here, we report an efficient, robust automated methodology for the installation of 3′-amino chemical modifications in DNA and RNA. Guided by a prospective computational analysis that identified a feasible pathway for linker fragmentation, we repurposed commercially available UnyLinker as an in situ functionalizable support for the automated synthesis of 3′-amino-modified DNA and RNA. Detritylation and conversion of the exposed UnyLinker hydroxyl group into a succinimidyl carbonate enable direct coupling of nucleosidic and non-nucleosidic amines, after which oligonucleotide assembly, cleavage, deprotection, and purification proceed using well-established protocols. Density functional theory calculations identify base-mediated E2 elimination followed by carbamate decarboxylation as the most favorable of the cleavage pathways examined. To the best of our knowledge, this is the first automated synthesis of 3′-amino modifiers directly on standard commercially available solid supports. This versatile methodology provides a general platform for the synthesis of amino-functionalized nucleic acids, enabling diverse applications in nucleic acid chemistry, chemical biology, and biotechnology with widespread applications in industry and academia.

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