Structure-activity relationships by interligand NOE-based design and synthesis of antiapoptotic compounds targeting Bid
Structure-activity relationships by interligand NOE-based design and synthesis of antiapoptotic compounds targeting Bid
复制标题
DOI：
10.1073/pnas.0603460103
复制
发表时间：
2006-08-15
影响因子：
11.1
通讯作者：
Pellecchia, Maurizio
中科院分区：
文献类型：
--
作者：
Becattini, Barbara;Culmsee, Carsten;Pellecchia, Maurizio
Bcl-2家族蛋白在组织稳态和细胞凋亡（程序性细胞死亡）中起关键作用。Bid是Bcl-2家族的促凋亡成员，被caspase-8激活后可促进细胞死亡。通过基于核磁共振的方法（通过配体间NOE的结构-活性关系），我们能够识别在Bid表面结合的两个化学片段。这两个片段的共价连锁导致了高亲和力的双齿衍生物。体外和细胞内实验表明，这些化合物可以阻止tBid易位到线粒体膜，随后释放促凋亡刺激，并在低微摩尔范围内抑制神经元凋亡。因此，通过使用合理的化学生物学方法，我们获得了抗凋亡化合物，这些化合物可能对与Bid激活相关的疾病具有治疗潜力，例如神经退行性疾病、脑缺血或脑创伤。
Bcl-2 family proteins play a crucial role in tissue homeostasis and apoptosis (programmed cell death). Bid is a proapoptotic member of the Bcl-2 family, promoting cell death when activated by caspase-8. Following an NMR-based approach (structure-activity relationships by interligand NOE) we were able to identify two chemical fragments that bind on the surface of Bid. Covalent linkage of the two fragments led to high-affinity bidentate derivatives. In vitro and in-cell assays demonstrate that the compounds prevent tBid translocation to the mitochondrial membrane and the subsequent release of proapoptotic stimuli and inhibit neuronal apoptosis in the low micromolar range. Therefore, by using a rational chemical-biology approach, we derived antiapoptotic compounds that may have a therapeutic potential for disorders associated with Bid activation, e.g., neurodegenerative diseases, cerebral ischemia, or brain trauma.