High-throughput screening identifies small molecules that enhance the pharmacological effects of oligonucleotides.
High-throughput screening identifies small molecules that enhance the pharmacological effects of oligonucleotides.
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DOI：
10.1093/nar/gkv060
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发表时间：
2015-02-27
影响因子：
14.9
通讯作者：
Juliano RL
中科院分区：
文献类型：
--
作者：
Yang B;Ming X;Cao C;Laing B;Yuan A;Porter MA;Hull-Ryde EA;Maddry J;Suto M;Janzen WP;Juliano RL
反义和siRNA寡核苷酸的治疗应用受到这些膜不通透分子到达其细胞内作用部位的有限能力的限制。我们试图解决这个问题，使用小的有机分子来通过调节寡核苷酸在细胞内的运输和从内体释放来增强其效果。多个小分子文库的高通量筛选产生了几次点击，显著增强了剪接开关寡核苷酸在细胞培养中的作用。这些化合物还增强了反义和siRNA寡核苷酸的作用。HIT化合物优先导致荧光寡核苷酸从较晚的内体释放，而不是其他细胞内隔室。在转基因小鼠模型中的研究表明，这些化合物可以增强剪接开关寡核苷酸的体内效应，而不会造成明显的毒性。这些观察表明，选定的小分子增强剂可能最终在基于寡核苷酸的治疗中有价值。
The therapeutic use of antisense and siRNA oligonucleotides has been constrained by the limited ability of these membrane-impermeable molecules to reach their intracellular sites of action. We sought to address this problem using small organic molecules to enhance the effects of oligonucleotides by modulating their intracellular trafficking and release from endosomes. A high-throughput screen of multiple small molecule libraries yielded several hits that markedly potentiated the actions of splice switching oligonucleotides in cell culture. These compounds also enhanced the effects of antisense and siRNA oligonucleotides. The hit compounds preferentially caused release of fluorescent oligonucleotides from late endosomes rather than other intracellular compartments. Studies in a transgenic mouse model indicated that these compounds could enhance the in vivo effects of a splice-switching oligonucleotide without causing significant toxicity. These observations suggest that selected small molecule enhancers may eventually be of value in oligonucleotide-based therapeutics.
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影响因子：
4.9
作者：
Juliano R;Bauman J;Kang H;Ming X
通讯作者：
Ming X
影响因子：
7.3
作者：
Kireev D;Wigle TJ;Norris-Drouin J;Herold JM;Janzen WP;Frye SV
通讯作者：
Frye SV
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.
影响因子：
8.8
作者：
Bianchini, D.;Omlin, A.;Pezaro, C.;Lorente, D.;Ferraldeschi, R.;Mukherji, D.;Crespo, M.;Figueiredo, I.;Miranda, S.;Riisnaes, R.;Zivi, A.;Buchbinder, A.;Rathkopf, D. E.;Attard, G.;Scher, H. I.;de Bono, J.;Danila, D. C.
通讯作者：
Danila, D. C.