Oligonucleotide-based telomerase inhibitors with a photoresponsive α-chloroaldehyde

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-02-20 DOI:10.1016/j.bmcl.2025.130138

Kentaro Kobata, Kazuki Matsubara, Risa Nishikawa, Yuki Narita, Kazuya Matsuo, Tomonori Waku, Akio Kobori

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Abstract

Telomerase, a ribonucleoprotein, is a reverse transcriptase that uses telomerase RNA component (hTR) as a template to elongate telomeric DNA at the ends of chromosomes. This enzyme plays a critical role in oncogenic cellular transformation. Therefore, the telomerase is considered an attractive target for cancer therapy. In this study, we synthesized photo-cross-linking oligodeoxyribonucleotides (ODNs) with a photoresponsive α-chloroaldehyde (PCA) moiety at the 3′-end or the 5′-end of the ODNs and evaluated the inhibition efficiencies for telomerase activity. PCA-modified ODNs with a sequence complementary to the template RNA of telomerase inhibited telomerase activity upon UV irradiation, whereas those with scramble sequence showed no significant inhibition. The 50 % inhibitory concentration (IC₅₀) of PCA-modified ODN was significantly reduced by UV irradiation. These results indicate that PCA-modified ODN inhibits telomerase activity in a sequence-selective manner and that the inhibitory activity is enhanced by the cross-linking reaction following UV irradiation.

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具有光反应性α-氯醛的端粒酶寡核苷酸抑制剂。

端粒酶是一种核糖核蛋白，是一种以端粒酶RNA组分（hTR）为模板，在染色体末端拉长端粒DNA的逆转录酶。这种酶在致癌细胞转化中起关键作用。因此，端粒酶被认为是癌症治疗的一个有吸引力的靶点。在本研究中，我们合成了在ODNs的3′端或5′端具有光响应性α-氯醛（PCA）片段的光交联寡脱氧核糖核苷酸（ODNs），并评估了其对端粒酶活性的抑制效率。具有端粒酶模板RNA互补序列的pca修饰odn对端粒酶活性有抑制作用，而具有scramble序列的odn对端粒酶活性无明显抑制作用。紫外辐照显著降低了pca修饰ODN的50 %抑制浓度（IC50）。这些结果表明，pca修饰的ODN以序列选择性的方式抑制端粒酶的活性，并通过紫外线照射后的交联反应增强了抑制活性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.