RNA 的 MOE 修饰：起源和对寡核苷酸治疗领域的广泛影响,Helvetica Chimica Acta

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RNA 的 MOE 修饰：起源和对寡核苷酸治疗领域的广泛影响
Helvetica Chimica Acta ( IF 1.5 ) Pub Date : 2023-01-11 , DOI: 10.1002/hlca.202200169
Jonathan Hall ₁ , Alyssa C. Hill ₂

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在Helvetica Chimica Acta于 1995 年发表的一篇文章中，化学家P. Martin描述了用于治疗性反义寡核苷酸 (ASO)的 2'- O-烷基化核糖核苷的合成。这项工作的动机是需要一种与固相合成方案兼容的修饰核糖结构，并且当将其掺入寡核苷酸时，将使其对核酸酶具有抗性，而不会削弱其与互补 RNA 靶标杂交的能力。Martin描述了一种可靠的 2'- O-烷基核糖核苷途径，其中核糖 2'-OH 基团被 2'-乙二醇衍生物取代。显示包含这些修饰的寡核苷酸überraschende Eigenschaften—— “令人惊讶的特性”——值得注意的是，相对于未修饰的对应物，对 RNA 底物的亲和力和特异性更高，对核酸酶的稳定性更高。如今，2'-乙二醇修饰在本领域被普遍称为 2'- O-甲氧基乙基 (MOE) 修饰。四种 ASO 药物和临床试验中的许多其他药物的化学特征。在这里，我们1 ) 总结了 MOE 修饰核糖的合成；2 ) 概述了Martin文章中报道的 MOE 修饰寡核苷酸的特性；3 ) 重点介绍第一个获批的 MOE 修饰的 ASO 药物 mipomersen 和 nusinersen；和4) 在临床开发中调查 MOE 修饰的 ASO。在展望中，我们将这些发展放在背景中，并考虑 MOE 修改的未来可能性。

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The MOE Modification of RNA: Origins and Widescale Impact on the Oligonucleotide Therapeutics Field

In an article published by Helvetica Chimica Acta in 1995, chemist P. Martin describes the synthesis of 2′-O-alkylated ribonucleosides for use in therapeutic antisense oligonucleotides (ASOs). This work was motivated by the need for a modified ribose structure that was compatible with solid-phase synthesis protocols and that, when incorporated into an oligonucleotide, would render it resistant to nucleases without attenuating its ability to hybridize to a complementary RNA target. Martin described a robust route to 2′-O-alkylribonucleosides in which the ribose 2′-OH group is substituted with 2′-ethylene glycol derivatives. Oligonucleotides containing these modifications displayed überraschende Eigenschaften – ‘surprising properties’ – notably, higher affinity and specificity for RNA substrates and greater stability to nucleases relative to their unmodified counterparts. Today, the 2′-ethylene glycol modification is universally known in the field as the 2′-O-methoxyethyl (MOE) modification. The chemistry features in four ASO drugs and many others in clinical trials. Here, we 1) summarize the synthesis of the MOE-modified ribose; 2) outline the properties of MOE-modified oligonucleotides as reported in Martin’s article; 3) highlight the first approved MOE-modified ASO drugs, mipomersen and nusinersen; and 4) survey MOE-modified ASOs in clinical development. In the outlook, we put these developments into context and consider future possibilities for the MOE modification.

更新日期：2023-01-11

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