A Novel CUGexp•MBNL1 Inhibitor with Therapeutic Potential for Myotonic Dystrophy Type 1

被引：52

作者：

Jahromi, Amin Haghighat ^{[1
,2
]}

Lien Nguyen ^{[2
]}

Fu, Yuan ^{[2
]}

Miller, Kali A. ^{[2
]}

Baranger, Anne M. ^{[2
]}

Zimmerman, Steven C. ^{[2
]}

机构：

[1] Univ Illinois, Ctr Biophys & Computat Biol, Urbana, IL 61801 USA

[2] Univ Illinois, Dept Chem, Urbana, IL 61801 USA

来源：

ACS CHEMICAL BIOLOGY | 2013年 / 8卷 / 05期

基金：

美国国家卫生研究院;

关键词：

PRE-MESSENGER-RNA; SMALL MOLECULES; TARGETING RNA; SPERMINE CONJUGATION; PATHOGENIC RNAS; CUG REPEATS; MBNL1; MUSCLEBLIND; RECOGNITION; REVERSAL;

D O I：

10.1021/cb400046u

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Myotonic dystrophy type 1 (DM1) is caused by an expanded CUG repeat (CUG(exp)) that sequesters muscleblind-like 1 protein (MBNL1), a protein that regulates alternative splicing. CUG(exp) RNA is a validated drug target for this currently untreatable disease. Herein, we develop a bioactive small molecule (1) that targets CUG(exp) RNA and is able to inhibit the CUG(exp)center dot MBNL1 interaction in cells that model DM1. The core of this small molecule is based on ligand 2, which was previously reported to be active in an in vitro assay. A polyamine-derivative side chain was conjugated to this core to make it aqueous-soluble and cell-penetrable. In a DM1 cell model this conjugate was found to disperse CUG(exp) ribonuclear foci, release MBNL1, and partially reverse the mis-splicing of the insulin receptor pre-mRNA. Direct evidence for ribonuclear foci dispersion by this ligand was obtained in a live DM1 cell model using time-lapse confocal microscopy.

引用

页码：1037 / 1043

页数：7

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