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Modified internucleoside linkages for nuclease-resistant oligonucleotides
RSC Chemical Biology ( IF 4.2 ) Pub Date : 2020-12-8 , DOI: 10.1039/d0cb00136h Guillaume Clavé 1 , Maeva Reverte 1 , Jean-Jacques Vasseur 1 , Michael Smietana 1
RSC Chemical Biology ( IF 4.2 ) Pub Date : 2020-12-8 , DOI: 10.1039/d0cb00136h Guillaume Clavé 1 , Maeva Reverte 1 , Jean-Jacques Vasseur 1 , Michael Smietana 1
Affiliation
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In the past few years, several drugs derived from nucleic acids have been approved for commercialization and many more are in clinical trials. The sensitivity of these molecules to nuclease digestion in vivo implies the need to exploit resistant non-natural nucleotides. Among all the possible modifications, the one concerning the internucleoside linkage is of particular interest. Indeed minor changes to the natural phosphodiester may result in major modifications of the physico-chemical properties of nucleic acids. As this linkage is a key element of nucleic acids’ chemical structures, its alteration can strongly modulate the plasma stability, binding properties, solubility, cell penetration and ultimately biological activity of nucleic acids. Over the past few decades, many research groups have provided knowledge about non-natural internucleoside linkage properties and participated in building biologically active nucleic acid derivatives. The recent renewing interest in nucleic acids as drugs, demonstrated by the emergence of new antisense, siRNA, aptamer and cyclic dinucleotide molecules, justifies the review of all these studies in order to provide new perspectives in this field. Thus, in this review we aim at providing the reader insights into modified internucleoside linkages that have been described over the years whose impact on annealing properties and resistance to nucleases have been evaluated in order to assess their potential for biological applications. The syntheses of modified nucleotides as well as the protocols developed for their incorporation within oligonucleotides are described. Given the intended biological applications, the modifications described in the literature that have not been tested for their resistance to nucleases are not reported.
中文翻译：
用于抗核酸酶寡核苷酸的修饰核苷间连接
过去几年，多种核酸衍生药物已获准商业化，还有更多药物正在进行临床试验。这些分子对体内核酸酶消化的敏感性意味着需要开发抗性非天然核苷酸。在所有可能的修饰中，有关核苷间连接的修饰特别令人感兴趣。事实上，天然磷酸二酯的微小变化可能导致核酸的物理化学性质的重大改变。由于这种连接是核酸化学结构的关键要素，因此它的改变可以强烈调节核酸的血浆稳定性、结合特性、溶解度、细胞渗透性和最终的生物活性。在过去的几十年里，许多研究小组提供了有关非天然核苷间连接特性的知识，并参与构建具有生物活性的核酸衍生物。新的反义、siRNA、适体和环状二核苷酸分子的出现证明了最近人们对核酸作为药物的兴趣重新燃起，这证明了对所有这些研究进行回顾的合理性，以便为该领域提供新的视角。因此，在这篇综述中，我们的目的是为读者提供对多年来描述的修饰核苷间连接的见解，这些连接对退火特性和核酸酶抗性的影响已得到评估，以评估其生物学应用的潜力。描述了修饰核苷酸的合成以及为将其掺入寡核苷酸而开发的方案。考虑到预期的生物学应用，文献中描述的未经核酸酶抗性测试的修饰并未被报道。
更新日期：2020-12-09
中文翻译：
用于抗核酸酶寡核苷酸的修饰核苷间连接
过去几年，多种核酸衍生药物已获准商业化，还有更多药物正在进行临床试验。这些分子对体内核酸酶消化的敏感性意味着需要开发抗性非天然核苷酸。在所有可能的修饰中，有关核苷间连接的修饰特别令人感兴趣。事实上，天然磷酸二酯的微小变化可能导致核酸的物理化学性质的重大改变。由于这种连接是核酸化学结构的关键要素，因此它的改变可以强烈调节核酸的血浆稳定性、结合特性、溶解度、细胞渗透性和最终的生物活性。在过去的几十年里，许多研究小组提供了有关非天然核苷间连接特性的知识，并参与构建具有生物活性的核酸衍生物。新的反义、siRNA、适体和环状二核苷酸分子的出现证明了最近人们对核酸作为药物的兴趣重新燃起，这证明了对所有这些研究进行回顾的合理性，以便为该领域提供新的视角。因此，在这篇综述中，我们的目的是为读者提供对多年来描述的修饰核苷间连接的见解，这些连接对退火特性和核酸酶抗性的影响已得到评估，以评估其生物学应用的潜力。描述了修饰核苷酸的合成以及为将其掺入寡核苷酸而开发的方案。考虑到预期的生物学应用，文献中描述的未经核酸酶抗性测试的修饰并未被报道。
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