Integrating Display and Delivery Functionality with a Cell Penetrating Peptide Mimic as a Scaffold for Intracellular Multivalent Multitargeting
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香港中文大學研究人員

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摘要The construction of a multivalent ligand is an effective way to increase affinty and selectivity toward biomolecular targets with multiple-ligand binding sites. Adopting this strategy, we used a known cell-penetrating peptide (CPP) mimic as a scaffold to develop a series of multivalent ligand constructs that bind to the expanded dCTG (CTG(exp)) and rCUG nucleotide repeats (CTG(exp)) known to cause myotonic dystrophy type I (DM1), an incurable neuromuscular disease. By assembling this polyvalent construct, the hydrophobic ligands are solubilized and delivered into cell nuclei, and their enhanced binding affinity leads to the inhibition of ribonuclear foci formation and a reversal of spiking defects, all at low concentrations. Some of the multivalent ligands are shown to inhibit selectively the in vitro transcription of (CTG-CAG)(74), to reduce the concentration of the toxic CUG RNA in DM1 model cells, and to show phenotypic improvement in vivo in a Drosophila model of DM1. This strategy may be useful in drug design for other trinucleotide repeat disorders and more broadly for intracellular multivalent targeting.
著者Bai YG, Nguyen L, Song ZY, Peng SH, Lee J, Zheng N, Kapoor I, Hagler LD, Cai KM, Cheng JJ, Chan HYE, Zimmerman SC
期刊名稱Journal of the American Chemical Society
出版年份2016
月份8
日期3
卷號138
期次30
出版社AMER CHEMICAL SOC
頁次9498 - 9507
國際標準期刊號0002-7863
語言英式英語
Web of Science 學科類別Chemistry; Chemistry, Multidisciplinary

上次更新時間 2021-17-02 於 01:33