Liczner Christopher, Hanna Cameron C, Payne Richard J, Wilds Christopher J
Department of Chemistry and Biochemistry, Concordia University 7141 Rue Sherbrooke Ouest Montréal Québec H4B 1R6 Canada
School of Chemistry, The University of Sydney Sydney NSW 2006 Australia.
Chem Sci. 2021 Nov 19;13(2):410-420. doi: 10.1039/d1sc04937b. eCollection 2022 Jan 5.
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 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 to generate diselenide dimer molecules. These can be rapidly ligated with peptide selenoesters and, following deselenization, lead to the efficient generation of POCs. The diselenide within the oligonucleotide also serves as a flexible functionalisation handle that can be leveraged for fluorescent labelling, as well as for alkylation to generate micelles.
需要多种策略来有效地用肽或脂质修饰寡核苷酸，以充分利用其治疗和诊断潜力，包括调节化学稳定性以及用于细胞靶向和细胞渗透性应用。肽寡核苷酸缀合物（POC）中通常使用的化学连接在稳定性和/或合成容易性方面存在局限性。在此，我们报告了一种使用二硒化物-硒酯连接（DSL）-脱硒策略进行POC合成的有效方法，该策略可在两种生物分子之间快速生成稳定的酰胺键。这种缀合策略以一种新型硒化物亚磷酰胺构建块为基础，该构建块可通过固相合成掺入寡核苷酸中以生成二硒化物二聚体分子。这些分子可以与肽硒酯快速连接，并在脱硒后有效地生成POC。寡核苷酸中的二硒化物还可作为一种灵活的功能化处理基团，可用于荧光标记以及烷基化以生成胶束。
