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Progress towards drug discovery for Friedreich's Ataxia: Identifying synthetic oligonucleotides that more potently activate expression of human frataxin protein.
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2020-04-05 , DOI: 10.1016/j.bmc.2020.115472
Xiulong Shen 1 , Johnathan Wong 1 , Thahza P Prakash 2 , Frank Rigo 2 , Yanjie Li 3 , Marek Napierala 3 , David R Corey 1
Affiliation  

Friedreich's Ataxia (FRDA) is an incurable genetic disease caused by an expanded trinucleotide AAG repeat within intronic RNA of the frataxin (FXN) gene. We have previously demonstrated that synthetic antisense oligonucleotides or duplex RNAs that are complementary to the expanded repeat can activate expression of FXN and return levels of FXN protein to near normal. The potency of these compounds, however, was too low to encourage vigorous pre-clinical development. We now report testing of "gapmer" oligonucleotides consisting of a central DNA portion flanked by chemically modified RNA that increases binding affinity. We find that gapmer antisense oligonucleotides are several fold more potent activators of FXN expression relative to previously tested compounds. The potency of FXN activation is similar to a potent benchmark gapmer targeting the nuclear noncoding RNA MALAT-1, suggesting that our approach has potential for developing more effective compounds to regulate FXN expression in vivo.

中文翻译:


弗里德赖希共济失调药物发现的进展:识别更有效地激活人类 frataxin 蛋白表达的合成寡核苷酸。



弗里德赖希共济失调 (FRDA) 是一种无法治愈的遗传病,由 frataxin (FXN) 基因内含子 RNA 内的三核苷酸 AAG 重复序列扩展引起。我们之前已经证明,与扩增的重复序列互补的合成反义寡核苷酸或双链体RNA可以激活FXN的表达并使FXN蛋白的水平恢复到接近正常水平。然而,这些化合物的效力太低,无法促进积极的临床前开发。我们现在报告了“gapmer”寡核苷酸的测试,该寡核苷酸由中央 DNA 部分组成,两侧是经过化学修饰的 RNA,可增加结合亲和力。我们发现,gapmer 反义寡核苷酸是 FXN 表达的有效激活剂,相对于之前测试的化合物要强几倍。 FXN 激活的效力类似于针对核非编码 RNA MALAT-1 的有效基准 gapmer,这表明我们的方法有潜力开发更有效的化合物来调节体内 FXN 表达。
更新日期:2020-04-05
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