Small molecules block the polymerization of Z α1-antitrypsin and increase the clearance of intracellular aggregates
Small molecules block the polymerization of Z α1-antitrypsin and increase the clearance of intracellular aggregates
复制标题
DOI：
10.1021/jm070687z
复制
发表时间：
2007-11-01
影响因子：
7.3
通讯作者：
Lomas, David A.
中科院分区：
文献类型：
--
作者：
Mallyat, Meera;Phillips, Russell L.;Lomas, David A.
(Xi-抗胰蛋白酶(Glu342Lys)的Z突变导致结构域交换和肝内聚合物的形成，这些聚合物聚集成包涵体，使纯合子容易患上肝硬变。我们已经确定了一种不同于聚合所涉及的界面的变构空腔，用于合理的基于结构的药物设计以阻止聚合物的形成。对120万个小分子进行了虚拟配体筛选，鉴定出6个化合物在体外减少了聚合物的形成。对配体结合对空腔的影响进行建模并重新筛选文库，发现了另外10种完全阻止聚合的化合物。在细胞疾病模型中，当化合物与Zα(1)-抗胰蛋白酶的比例为2.5：1时，最好的拮抗剂可使Zα-抗胰蛋白酶在细胞内的积聚减少70%。识别小分子为治疗与α-1-抗胰蛋白酶Z等位基因相关的肝病提供了一种新的治疗方法。
The Z mutant of (xi-antitrypsin (Glu342Lys) causes a domain swap and the formation of intrahepatic polymers that aggregate as inclusions and predispose the homozygote to cirrhosis. We have identified an allosteric cavity that is distinct from the interface involved in polymerization for rational structure-based drug design to block polymer formation. Virtual ligand screening was performed on 1.2 million small molecules and 6 compounds were identified that reduced polymer formation in vitro. Modeling the effects of ligand binding on the cavity and re-screening the library identified an additional 10 compounds that completely blocked polymerization. The best antagonists were effective at ratios of compound to Z alpha(1)-antitrypsin of 2.5:1 and reduced the intracellular accumulation of Z a,-antitrypsin by 70% in a cell model of disease. Identifying small molecules provides a novel therapy for the treatment of liver disease associated with the Z allele of alpha-1-antitrypsin.