Programmable siRNA pro-drugs that activate RNAi activity in response to specific cellular RNA biomarkers.
Programmable siRNA pro-drugs that activate RNAi activity in response to specific cellular RNA biomarkers.
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DOI：
10.1016/j.omtn.2021.12.039
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发表时间：
2022-03-08
期刊：
影响因子：
--
通讯作者：
Goddard WA 3rd
中科院分区：
文献类型：
--
作者：
Han SP;Scherer L;Gethers M;Salvador AM;Salah MBH;Mancusi R;Sagar S;Hu R;DeRogatis J;Kuo YH;Marcucci G;Das S;Rossi JJ;Goddard WA 3rd
自从保罗埃利希在1908年提出“魔术子弹”概念以来，药物开发人员一直在寻找新的方法来靶向病变细胞的药物活性，同时限制对正常组织的影响。近年来，有人提出将能够检测RNA生物标志物的核糖开关偶联到小干扰RNA（siRNA）以产生siRNA前药可以选择性地激活特定细胞中的RNA干扰（RNAi）活性。然而，这一概念以前并没有实现。我们在这里报告说，我们已经实现了这一目标，验证了一个简单和可编程的新设计，在哺乳动物细胞中可靠地发挥作用。我们表明，这些条件激活的siRNA（Cond-siRNA）可以响应不同的细胞RNA生物标志物，在明显区分的OFF和ON状态之间切换针对不同靶标的RNAi活性。值得注意的是，在大鼠心肌细胞系（H9 C2）中，我们的构建体的一个版本表现出对心脏病相关靶基因蛋白磷酸酶3催化亚基α（PPP 3CA）的生物学意义的抑制，以响应病理标志物心房利钠肽（NPPA）信使RNA（mRNA）的表达增加。我们的研究结果证明了合成核糖开关在哺乳动物细胞中调节基因表达的能力，为可编程siRNA前药的开发开辟了新的途径。我们报道了条件激活的小干扰RNA的发展。这些可编程的寡核苷酸前药仅响应于哺乳动物细胞中特定RNA生物标志物的存在而激活针对靶基因的RNAi活性。这为将药物活性靶向特定细胞群体而不影响非靶组织开辟了新的途径。
Since Paul Ehrlich’s introduction of the “magic bullet” concept in 1908, drug developers have been seeking new ways to target drug activity to diseased cells while limiting effects on normal tissues. In recent years, it has been proposed that coupling riboswitches capable of detecting RNA biomarkers to small interfering RNAs (siRNAs) to create siRNA pro-drugs could selectively activate RNA interference (RNAi) activity in specific cells. However, this concept has not been achieved previously. We report here that we have accomplished this goal, validating a simple and programmable new design that functions reliably in mammalian cells. We show that these conditionally activated siRNAs (Cond-siRNAs) can switch RNAi activity against different targets between clearly distinguished OFF and ON states in response to different cellular RNA biomarkers. Notably, in a rat cardiomyocyte cell line (H9C2), one version of our construct demonstrated biologically meaningful inhibition of a heart-disease-related target gene protein phosphatase 3 catalytic subunit alpha (PPP3CA) in response to increased expression of the pathological marker atrial natriuretic peptide (NPPA) messenger RNA (mRNA). Our results demonstrate the ability of synthetic riboswitches to regulate gene expression in mammalian cells, opening a new path for development of programmable siRNA pro-drugs. We report development of conditionally activated small interfering RNAs. These programmable oligonucleotide pro-drugs activate RNAi activity against target genes only in response to the presence of specific RNA biomarkers in mammalian cells. This opens new avenues for targeting drug activity to specific cell populations while sparing non-target tissues.
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DOI：
10.1021/jp408909t
发表时间：
2014-02-06
期刊：
The journal of physical chemistry. B
影响因子：
--
作者：
Condon DE;Yildirim I;Kennedy SD;Mort BC;Kierzek R;Turner DH
通讯作者：
Turner DH
影响因子：
5.5
作者：
Aduri, Raviprasad;Psciuk, Brian T.;SantaLucia, John, Jr.
通讯作者：
SantaLucia, John, Jr.
影响因子：
15
作者：
Kumar, Deepak;Kim, Sang Hoon;Yokobayashi, Yohei
通讯作者：
Yokobayashi, Yohei
影响因子：
3
作者：
Duan, Y;Wu, C;Kollman, P
通讯作者：
Kollman, P
影响因子：
10.8
作者：
Bindewald E;Afonin KA;Viard M;Zakrevsky P;Kim T;Shapiro BA
通讯作者：
Shapiro BA