Investigation of Sequence-Penetration Relationships of Antisense Oligonucleotides.
Investigation of Sequence-Penetration Relationships of Antisense Oligonucleotides.
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反义寡核苷酸的序列渗透关系的研究。
DOI：
10.1002/cbic.202300009
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Kritzer,JoshuaA
中科院分区：
文献类型：
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作者：
Batistatou,Nefeli;Kritzer,JoshuaA
发展更有效的寡核苷酸疗法的一个主要限制是缺乏对它们渗透到细胞质中的理解。虽然先前的工作已经表明主链修饰如何影响细胞质渗透，但尚不清楚其他特征（包括碱基组成、碱基序列、长度和二级结构程度）如何影响细胞质渗透。我们已经应用氯烷烃渗透试验，该试验专门报告到达细胞质的物质，来研究这些特性对药物样寡核苷酸细胞质摄取的影响。我们发现碱基组成和碱基序列对细胞质渗透程度有中等影响，而长度与细胞质渗透程度没有直接相关。进一步调查，我们发现二级结构的程度与细胞质渗透有最大和最可预测的相关性。这些方法和观察增加了一层设计，以最大限度地提高新的寡核苷酸治疗的疗效。
A major limitation for the development of more effective oligonucleotide therapeutics has been a lack of understanding of their penetration into the cytosol. While prior work has shown how backbone modifications affect cytosolic penetration, it is unclear how cytosolic penetration is affected by other features including base composition, base sequence, length, and degree of secondary structure. We have applied the chloroalkane penetration assay, which exclusively reports on material that reaches the cytosol, to investigate the effects of these characteristics on the cytosolic uptake of druglike oligonucleotides. We found that base composition and base sequence had moderate effects, while length did not correlate directly with the degree of cytosolic penetration. Investigating further, we found that the degree of secondary structure had the largest and most predictable correlations with cytosolic penetration. These methods and observations add a layer of design for maximizing the efficacy of new oligonucleotide therapeutics.