Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.
National Magnetics Resonance Facility at Madison, Biochemistry Department, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States.
Biochemistry. 2020 Sep 22;59(37):3463-3472. doi: 10.1021/acs.biochem.0c00472. Epub 2020 Sep 10.
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) or r(CUG) 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.
目前，快速发现多靶标药物的方法较少。在此，我们描述了一种模板辅助、基于靶标的小分子发现方法，这些小分子可以识别导致 1 型肌强直性营养不良的扩展 d(CTG·CAG)序列及其 r(CUG)转录物中的 d(CTG)。使用能够产生>5000 种可能的二聚体和三聚体点击产物的 30 个单体炔基和叠氮化物小分子文库进行了正交叉选择。将单体在生理条件下与 d(CTG)或 r(CUG)孵育，这两个序列都表现出在邻近加速的叠氮-炔烃[3+2]环加成点击反应中的选择性。在两种选择中形成的点击产物数量有限，并且共同产物的数量更少，这表明该方法是发现单靶标和多靶标治疗剂的有用工具。
