Smetsers T F, Boezeman J B, Mensink E J
Department of Hematology, University Hospital St. Radboud, Nijmegen, The Netherlands.
Antisense Nucleic Acid Drug Dev. 1996 Spring;6(1):63-7. doi: 10.1089/oli.1.1996.6.63.
In this study we investigated if specific sequence motifs occur with a higher frequency in antisense oligonucleotides than can be expected on the basis of the mRNA composition to get an impression of the importance of these motifs for antisense effects. Computer analysis of 206 antisense oligonucleotides extracted from the literature and from sequence databases, all targeted against human mRNA, was performed. We compared the sequence composition of these oligonucleotides with the average of 100 equally large and randomly selected sequences from sequence databases and of their target mRNA. We found that the frequency of sequence motifs containing GG, CCC, CC, GAC, and CG is significantly higher and TT and that TCC is significantly lower in antisense oligonucleotide sequences than in the randomly selected mRNA sequences. We conclude that there is a bias in the nucleotide composition of antisense oligonucleotides. Some of these biased sequence motifs have been reported to induce nonantisense effects mediated by protein binding. Further analysis of the biologic function of these motifs is necessary to investigate if they should be avoided or incorporated into future designs of therapeutic effective oligonucleotides.
在本研究中，我们调查了特定序列基序在反义寡核苷酸中出现的频率是否高于基于mRNA组成所预期的频率，以了解这些基序对反义效应的重要性。我们对从文献和序列数据库中提取的206条均靶向人类mRNA的反义寡核苷酸进行了计算机分析。我们将这些寡核苷酸的序列组成与从序列数据库中随机选择的100条同样大小的序列及其靶mRNA的平均值进行了比较。我们发现，与随机选择的mRNA序列相比，反义寡核苷酸序列中含有GG、CCC、CC、GAC和CG的序列基序频率显著更高，而含有TT和TCC的序列基序频率显著更低。我们得出结论，反义寡核苷酸的核苷酸组成存在偏差。据报道，其中一些有偏差的序列基序会诱导由蛋白质结合介导的非反义效应。有必要对这些基序的生物学功能进行进一步分析，以研究是否应避免这些基序或将其纳入未来治疗有效寡核苷酸的设计中。
