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用多个LNA-phosphothiotriester脊柱进行拼接切换的寡核酸的合成,生物物理和生物评估

Debashis Dhara¹, Alyssa C Hill², Abinaya Ramesh²

¹Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, U.K.

Journal of the American Chemical Society

|October 14, 2024

概括

开发具有增强稳定性和生物可用性的新型未充电的寡核酸对于向RNA的药物至关重要. 这项研究呈现了电荷中性LNA基三骨架,克服了治疗应用的合成限制.

科学领域:

医学化学
核酸化学
提供药物

背景情况:

聚离子反感寡核酸具有治疗潜力,但其生物可用性较差.
开发未充电的寡核酸骨干是改善药物输送的有希望的策略.
现有的合成未充电基骨的方法是有限的.

研究的目的:

合成和描述具有中性电荷的LNA基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基
评估这些改性寡核酸的稳定性,抗核酶性和治疗潜力.
探索用于增强分娩和细胞活动的结合策略.

主要方法:

固相合成具有不同三链接的寡核酸.
基于基组性质 (初级,二级,三级) 的合成成功的评估.
在真核细胞中评估双重稳定性,核酶抵抗性和拼接切换活性.
铜催化酸环添加 (CuAAC) 点击化学用于结合.

主要成果:

二次三链表现出稳定性,并允许大量的试剂.
经过修改的寡核酸具有与RNA的优异双重稳定性和强大的核酶抗性.
具有LNA-THP基酸的寡核酸有效地切换了真核细胞中的mRNA前拼接.
通过点击化学,基三聚使脂质,碳水化合物和小分子结合起来.

结论:

电荷中性LNA基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基基
这些修改显著提高了稳定性和核酶耐药性,解决了治疗用途的关键限制.
合成灵活性和已证明的拼接切换活性凸显了这些寡核酸在向RNA治疗中的潜力.

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Splicing is the process by which eukaryotic RNA is edited before its translation into protein. The RNA strand transcribed from eukaryotic DNA is called the primary transcript. The primary transcripts that become mRNAs are called precursor messenger RNAs (pre-mRNAs). Eukaryotic pre-mRNA contains alternating sequences of exons and introns. Exons are nucleotide sequences that code for proteins, whereas introns are the non-coding regions. In RNA splicing, introns are removed and exons are bonded...

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