Towards combining backbone and sugar constraint in 3′-3′ bis-phosphonate tethered 2′-4′ bridged LNA oligonucleotide trimers,RSC Advances

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Towards combining backbone and sugar constraint in 3′-3′ bis-phosphonate tethered 2′-4′ bridged LNA oligonucleotide trimers
RSC Advances ( IF 3.9 ) Pub Date : 2024-07-26 , DOI: 10.1039/d4ra04277h
Edouard Duchamp ₁ , Guillermo Vasquez ₂ , Neda Firoozi ₁ , Graeme C Freestone ₂ , Michael Oestergaard ₂ , Punit P Seth ₃ , Stephen Hanessian _{1,

4}

Affiliation

Therapeutic oligonucleotides are chemically modified to enhance their drug-like properties – including binding affinity for target RNA. Many nucleic acid analogs that enhance RNA binding affinity constrain the furanose sugar in an RNA-like sugar pucker. The improvements in binding affinity result primarily from increased off-rates with minimal effects on on-rates for hybridization. To identify alternate chemical modification strategies that can modulate on- and off-rates for oligonucleotide hybridization, we hypothesized that extending conformational restraint across multiple nucleotides could modulate hybridization kinetics by restricting rotational freedom of the sugar-phosphate backbone. As part of that effort, we recently reported that using hydrocarbon tethers to bridge adjacent phosphodiester linkages as phosphonate tethered bridges can pre-organize nucleic acids in conformations conducive for Watson–Crick base-pairing and modulate hybridization kinetics. In this report, we describe the synthesis of locked nucleic acid (LNA) trimers linked through alkylphosphonate tethers which restrict conformation of the furanose sugar in addition to restricting conformational mobility of the sugar-phosphate backbone across three nucleotide units.

中文翻译：

致力于将 3'-3' 双膦酸酯系链的 2'-4' 桥接 LNA 寡核苷酸三聚体中的主链和糖约束相结合

治疗性寡核苷酸经过化学修饰，以增强其药物特性，包括与靶标 RNA 的结合亲和力。许多增强RNA结合亲和力的核酸类似物将呋喃糖限制在RNA样糖褶皱中。结合亲和力的提高主要是由于解离速率的增加，而对杂交的结合速率的影响最小。为了确定可以调节寡核苷酸杂交的结合和解离速率的替代化学修饰策略，我们假设跨多个核苷酸扩展构象限制可以通过限制糖-磷酸骨架的旋转自由度来调节杂交动力学。作为这项工作的一部分，我们最近报道，使用烃系链作为膦酸酯系链桥来桥接相邻的磷酸二酯键可以将核酸预组织成有利于沃森-克里克碱基配对的构象并调节杂交动力学。在本报告中，我们描述了通过烷基膦酸酯系链连接的锁核酸（LNA）三聚体的合成，该三聚体除了限制糖-磷酸骨架跨三个核苷酸单元的构象流动性之外，还限制呋喃糖的构象。

更新日期：2024-07-26

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