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在内皮细胞中准miR-214-3p的化学修饰的反感性寡核酸的结构和功能表征

Elisabetta Caiazzo¹, Pietro Delre², Carmen Cerchia²

¹Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, via Domenico Montesano 49, I-80131 Naples, Italy; School of Infection & Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.

Bioorganic chemistry

|December 9, 2025

概括

研究人员开发了新的反感性寡核化物 (ASO),以准miR-214-3p,这是内皮功能障碍的关键因素. 主要候选物,ASO-60,通过恢复内皮功能来治疗心血管疾病有希望.

科学领域:

生物化学生化学
分子生物学分子生物学
药理学药理学是指药理学的学科.

背景情况:

微RNA-214-3p (miR-214-3p) 失调与内皮功能障碍和心血管疾病有关.
miR-214-3p调节关键通路,包括氧化应激,血管炎症和内皮氧化合成酶 (eNOS) 相关的血管扩张.

研究的目的:

设计和评估具有锁定核酸 (LNA) 或2'-O-甲乙烯 (MOE) 修饰的新型反感性寡核酸 (ASO),以抑制miR-214-3p.
确定一个主要的ASO候选人,增强稳定性,目标参与和功能疗效,用于潜在的心血管治疗.

主要方法:

设计和合成八个ASO,包括LNA/MOE修改.
宏分子和物理化学表征:化温度 (Tm) 预测,分子动力学 (MD) 模拟,循环二元化 (CD) 热稳定性和核酶降解试验.
在人静脉内皮细胞 (HUVECs) 的体外功能评估,评估eNOS表达和基因调节.

主要成果:

与商用抑制剂相比,LNA和MOE修改显著改善了双重稳定性和核酶耐药性.
ASO-60表现出优越的热力学稳定性和目标结合亲和力.
ASO-60有效地恢复了HUVEC中的eNOS表达和其他内皮基因功能,超过了参考抑制剂.

结论:

化学修饰的ASO,特别是ASO-60,通过向miR-214-3p,为心血管疾病提供了一个有前途的治疗策略.
对寡核酸性质的全面表征对于优化治疗潜力和将结构设计与临床应用联系起来至关重要.

关键词:

2′-O-甲基乙烯 (MOE) 的使用.反意义的寡核化物.心血管治疗的治疗方法内皮氧化合成酶 (eNOS) 的作用锁定核酸 (LNA) 的使用在 miR-214-3p 中使用.

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MicroRNA (miRNA) are short, regulatory RNA transcribed from introns—non-coding regions of a gene—or intergenic regions—stretches of DNA present between genes. Several processing steps are required to form biologically active, mature miRNA. The initial transcript, called primary miRNA (pri-mRNA), base-pairs with itself forming a stem-loop structure. Within the nucleus, an endonuclease enzyme, called Drosha, shortens the stem-loop structure into hairpin-shaped pre-miRNA. After...