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Identification and characterization of small molecule inhibitors of the LINE-1 retrotransposon endonuclease
Nature Communications ( IF 14.7 ) Pub Date : 2024-05-08 , DOI: 10.1038/s41467-024-48066-x
Alexandra M D'Ordine 1, 2 , Gerwald Jogl 1, 2 , John M Sedivy 1, 2
Affiliation  

The long interspersed nuclear element-1 (LINE-1 or L1) retrotransposon is the only active autonomously replicating retrotransposon in the human genome. L1 harms the cell by inserting new copies, generating DNA damage, and triggering inflammation. Therefore, L1 inhibition could be used to treat many diseases associated with these processes. Previous research has focused on inhibition of the L1 reverse transcriptase due to the prevalence of well-characterized inhibitors of related viral enzymes. Here we present the L1 endonuclease as another target for reducing L1 activity. We characterize structurally diverse small molecule endonuclease inhibitors using computational, biochemical, and biophysical methods. We also show that these inhibitors reduce L1 retrotransposition, L1-induced DNA damage, and inflammation reinforced by L1 in senescent cells. These inhibitors could be used for further pharmacological development and as tools to better understand the life cycle of this element and its impact on disease processes.



中文翻译:


LINE-1 逆转录转座子核酸内切酶小分子抑制剂的鉴定和表征



长散布核元件-1(LINE-1或L1)反转录转座子是人类基因组中唯一活跃的自主复制反转录转座子。 L1 通过插入新拷贝、产生 DNA 损伤并引发炎症来伤害细胞。因此,L1 抑制可用于治疗与这些过程相关的许多疾病。由于相关病毒酶的特征良好的抑制剂的普遍存在,先前的研究主要集中在 L1 逆转录酶的抑制上。在这里,我们提出 L1 核酸内切酶作为降低 L1 活性的另一个靶点。我们使用计算、生物化学和生物物理方法表征结构多样的小分子核酸内切酶抑制剂。我们还表明,这些抑制剂可减少衰老细胞中 L1 逆转录转座、L1 诱导的 DNA 损伤以及 L1 增强的炎症。这些抑制剂可用于进一步的药理学开发,并作为更好地了解该元素的生命周期及其对疾病过程影响的工具。

更新日期:2024-05-09
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