Two-component covalent inhibitor.
Two-component covalent inhibitor.
复制标题
双组分共价抑制剂。
DOI：
10.1016/j.bmc.2013.01.021
复制
发表时间：
2013
影响因子：
3.5
通讯作者：
Kolpashchikov,DmitryM
中科院分区：
文献类型：
--
作者：
Cornett,EvanM;Gerasimova,YuliaV;Kolpashchikov,DmitryM
共价损伤蛋白质或核酸的抑制剂具有很强的效力，但难以合理设计，且特异性较差。在这里，我们概述了构建共价抑制剂的一般概念，称为双组分共价抑制剂(TCCI)。该方法利用了两个配备了预反应基团的配体类似物。类似物与目标生物聚合物的相邻位置的结合使预反应基团非常接近，并导致它们之间的相互作用，随后目标的共价损伤。在目前的研究中，我们使用光激活的预反应基团来灭活DNA聚合酶。研究发现，在非靶蛋白存在的情况下，传统的单组分抑制剂的效率大大降低，而TCCI没有明显的影响。我们的发现表明，TCCI方法在灭活复杂多组分系统中的生物聚合物方面具有优势。
Inhibitors that covalently damage proteins or nucleic acids offer great potency, but are difficult to rationally design and suffer from poor specificity. Here we outline a general concept for constructing covalent inhibitors, called the two-component covalent inhibitor (TCCI). The approach takes advantage of two ligand analogs equipped with pre-reactive groups. Binding of the analogs to the adjacent sites of a target biopolymer brings the pre-reactive groups in close proximity and causes their interaction followed by covalent damage of the target. In the present study we used light-activated pre-reactive groups to inactivate a DNA polymerase. It was found that the efficiency of a traditional single-component inhibitor was greatly reduced in the presence of a non-target protein, while the TCCI was not significantly affected. Our findings suggest that TCCI approach has advantages in inactivation of biopolymers in complex multi-component systems.