The small molecule Retro-1 enhances the pharmacological actions of antisense and splice switching oligonucleotides.
The small molecule Retro-1 enhances the pharmacological actions of antisense and splice switching oligonucleotides.
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DOI：
10.1093/nar/gkt066
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发表时间：
2013-04-01
影响因子：
14.9
通讯作者：
Juliano RL
中科院分区：
文献类型：
--
作者：
Ming X;Carver K;Fisher M;Noel R;Cintrat JC;Gillet D;Barbier J;Cao C;Bauman J;Juliano RL
由于寡核苷酸分子无法到达胞浆或细胞核中的作用位点，寡核苷酸难以发挥强大的药理作用。用脂质或聚合物输送系统解决这个问题的尝试只取得了部分成功。在这里，我们描述了一种新的替代方法，涉及使用无毒小分子来增强寡核苷酸的药理作用。这种化合物逆转录-1是在筛选小分子时发现的，这种小分子可以减少细菌毒素的作用，并被证明可以阻断逆行运输途径。我们证明逆转录-1也可以在细胞培养中显著增强反义和剪接开关寡核苷酸的有效性。这种效应发生在细胞内运输或加工水平，与细胞核中寡核苷酸积累增加有关，但不涉及溶酶体室室的扰动。我们还表明，retro1可以在体内改变剪接开关寡核苷酸的有效性。这些观察结果表明，使用无毒和非溶酶体性小分子佐剂可以增强寡核苷酸的药理作用。
The attainment of strong pharmacological effects with oligonucleotides is hampered by inefficient access of these molecules to their sites of action in the cytosol or nucleus. Attempts to address this problem with lipid or polymeric delivery systems have been only partially successful. Here, we describe a novel alternative approach involving the use of a non-toxic small molecule to enhance the pharmacological effects of oligonucleotides. The compound Retro-1 was discovered in a screen for small molecules that reduce the actions of bacterial toxins and has been shown to block the retrograde trafficking pathway. We demonstrate that Retro-1 can also substantially enhance the effectiveness of antisense and splice switching oligonucleotides in cell culture. This effect occurs at the level of intracellular trafficking or processing and is correlated with increased oligonucleotide accumulation in the nucleus but does not involve the perturbation of lysosomal compartments. We also show that Retro-1 can alter the effectiveness of splice switching oligonucleotides in the in vivo setting. These observations indicate that it is possible to enhance the pharmacological actions of oligonucleotides using non-toxic and non-lysosomotropic small molecule adjuncts.
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影响因子：
46.9
作者：
Dassie, Justin P.;Liu, Xiu-ying;Thomas, Gregory S.;Whitaker, Ryan M.;Thiel, Kristina W.;Stockdale, Katie R.;Meyerholz, David K.;McCaffrey, Anton P.;McNamara, James O., II;Giangrande, Paloma H.
通讯作者：
Giangrande, Paloma H.
影响因子：
4.7
作者：
Alam, Md Rowshon;Ming, Xin;Fisher, Michael;Lackey, Jeremy G.;Rajeev, Kallanthottathil G.;Manoharan, Muthiah;Juliano, Rudy L.
通讯作者：
Juliano, Rudy L.
RAB GTPases在膜交通和细胞生理学中的作用。
影响因子：
33.6
作者：
Hutagalung AH;Novick PJ
通讯作者：
Novick PJ
DOI：
10.1111/j.1432-1033.1997.00104.x
发表时间：
1997-08-15
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Eytan, GD;Regev, R;Assaraf, YG
通讯作者：
Assaraf, YG
影响因子：
3.2
作者：
Georgianna, Wesleigh E.;Young, Douglas D.
通讯作者：
Young, Douglas D.