Expanded DNA and RNA Trinucleotide Repeats in Myotonic Dystrophy Type 1 Select Their Own Multitarget, Sequence-Selective Inhibitors.,Biochemistry

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Expanded DNA and RNA Trinucleotide Repeats in Myotonic Dystrophy Type 1 Select Their Own Multitarget, Sequence-Selective Inhibitors.
Biochemistry ( IF 2.9 ) Pub Date : 2020-08-28 , DOI: 10.1021/acs.biochem.0c00472
Lauren D Hagler ₁ , Long M Luu ₁ , Marco Tonelli ₂ , JuYeon Lee ₁ , Samuel M Hayes ₃ , Sarah E Bonson ₁ , J Ignacio Vergara ₁ , Samuel E Butcher ₃ , Steven C Zimmerman ₁

Affiliation

There are few methods available for the rapid discovery of multitarget drugs. Herein, we describe the template-assisted, target-guided discovery of small molecules that recognize d(CTG) in the expanded d(CTG·CAG) sequence and its r(CUG) transcript that cause myotonic dystrophy type 1. A positive cross-selection was performed using a small library of 30 monomeric alkyne- and azide-containing ligands capable of producing >5000 possible di- and trimeric click products. The monomers were incubated with d(CTG)₁₆ or r(CUG)₁₆ under physiological conditions, and both sequences showed selectivity in the proximity-accelerated azide–alkyne [3+2] cycloaddition click reaction. The limited number of click products formed in both selections and the even smaller number of common products suggests that this method is a useful tool for the discovery of single-target and multitarget lead therapeutic agents.

中文翻译：

1 型强直性营养不良中扩增的 DNA 和 RNA 三核苷酸重复序列选择它们自己的多靶点序列选择性抑制剂。

可用于快速发现多靶点药物的方法很少。在此，我们描述了模板辅助、靶标引导的小分子发现，这些小分子识别扩展的 d(CTG·CAG) 序列中的 d(CTG) 及其导致 1 型强直性肌营养不良症的 r(CUG) 转录本。使用能够产生 > 5000 种可能的二聚体和三聚体点击产物的 30 个单体炔烃和叠氮化物配体的小型文库进行选择。将单体与 d(CTG) ₁₆或 r(CUG) ₁₆一起温育在生理条件下，两个序列在邻近加速的叠氮化物-炔烃 [3+2] 环加成点击反应中均显示出选择性。两种选择中形成的点击产品数量有限，而普通产品的数量甚至更少，这表明该方法是发现单靶点和多靶点先导治疗剂的有用工具。

更新日期：2020-09-22

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