DNA Analogues Modified at the Nonlinking Positions of Phosphorus.,Accounts of Chemical Research

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DNA Analogues Modified at the Nonlinking Positions of Phosphorus.
Accounts of Chemical Research ( IF 16.4 ) Pub Date : 2020-09-04 , DOI: 10.1021/acs.accounts.0c00078
Pawan Kumar ₁ , Marvin H Caruthers ₂

Affiliation

Chemically modified oligonucleotides are being developed as a new class of medicines for curing conditions that previously remained untreatable. Three primary classes of therapeutic oligonucleotides are single-stranded antisense oligonucleotides (ASOs), double stranded small interfering RNAs (siRNAs), and oligonucleotides that induce exon skipping. Recently, ASOs, siRNAs, and exon skipping oligonucleotides have been approved for patients with unmet medical needs, and many other candidates are being tested in late stage clinical trials. In coming years, therapeutic oligonucleotides may match the promise of small molecules and antibodies. Interestingly, in the 1980s when we developed chemical methods for synthesizing oligonucleotides, no one would have imagined that these highly charged macromolecules could become future medicines. Indeed, the anionic nature and poor metabolic stability of the natural phosphodiester backbone provided a major challenge for the use of oligonucleotides as therapeutic drugs. Thus, chemical modifications of oligonucleotides were essential in order to improve their pharmacokinetic properties. Keeping this view in mind, my laboratory has developed a series of novel oligonucleotides where one or both nonbridging oxygens in the phosphodiester backbone are replaced with an atom or molecule that introduces molecular properties that enhance biological activity. We followed two complementary approaches. One was the use of phosphoramidites that could act directly as synthons for the solid phase synthesis of oligonucleotide analogues. This approach sometimes was not feasible due to instability of various synthons toward the reagents used during synthesis of oligonucleotides. Therefore, using a complementary approach, we developed phosphoramidite synthons that can be incorporated into oligonucleotides with minimum changes in the solid phase DNA synthesis protocols but contain a handle for generating appropriate analogues postsynthetically.

中文翻译：

在磷的非连接位置修饰的DNA类似物。

化学修饰的寡核苷酸正被开发为一类用于治疗以前无法治愈的疾病的新型药物。治疗性寡核苷酸的三大主要类别是单链反义寡核苷酸（ASO），双链小干扰RNA（siRNA）和诱导外显子跳跃的寡核苷酸。最近，ASO，siRNA和外显子跳过寡核苷酸已被批准用于医疗需求未满足的患者，许多其他候选药物正在后期临床试验中进行测试。未来几年，治疗性寡核苷酸可能会与小分子和抗体的前景相符。有趣的是，在1980年代，当我们开发出合成寡核苷酸的化学方法时，没有人会想到这些高电荷的大分子可以成为未来的药物。确实，天然磷酸二酯主链的阴离子性质和较差的代谢稳定性为将寡核苷酸用作治疗药物提出了重大挑战。因此，寡核苷酸的化学修饰对于改善其药代动力学性质是必不可少的。牢记这一观点，我的实验室开发了一系列新颖的寡核苷酸，其中磷酸二酯主链中的一个或两个非桥接氧被一个引入增强生物学活性的分子特性的原子或分子取代。我们遵循两种互补的方法。一种是使用亚磷酰胺，其可直接作为合成子用于寡核苷酸类似物的固相合成。由于各种合成子对寡核苷酸合成过程中所用试剂的不稳定性，因此该方法有时不可行。因此，使用互补方法，我们开发了亚磷酰胺合成子，可以将其掺入到寡核苷酸中，而固相DNA合成方案的变化最小，但包含合成后生成合适类似物的手柄。

更新日期：2020-10-21

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