Midzak Andrew S, Akula Nagaraju, Rone Malena B, Papadopoulos Vassilios
The Research Institute of the McGill University Health Centre and Department of Medicine, McGill University, Montreal, Quebec, Canada.
The Research Institute of the McGill University Health Centre and Department of Medicine, McGill University, Montreal, Quebec, Canada; Departments of Biochemistry and Pharmacology & Therapeutics, McGill University, Montreal, Quebec, Canada.
Pharmacol Res. 2015 Sep;99:393-403. doi: 10.1016/j.phrs.2015.03.023. Epub 2015 Apr 29.
Mitochondria play a critical role in the physiological homeostasis of the cell, contributing to numerous cellular processes, including bioenergetics, metabolism and cell life and death. Owing to their keystone role, mitochondria have gained much attention as pharmacological targets. The outer mitochondrial integral membrane translocator protein (TSPO) has attracted a significant degree of pharmacological interest owing to its ability to bind a number of classes of drugs with high affinity and specificity. In addition to its well-characterized drug binding site, TSPO possess an additional high-affinity ligand binding site, originally identified for its ability to bind the lipid cholesterol, which was named the cholesterol recognition/interaction amino acid consensus (CRAC) motif. Previous investigations from our laboratory identified additional ligands targeted to TSPO's CRAC motif which are able to potently inhibit mitochondrial cholesterol transport and steroid biosynthesis, processes for which TSPO has been well-characterized. However, all of these compounds possessed the steroidal backbone common to cholesterol and steroid hormones. In our efforts to expand our understanding of TSPO's CRAC motif, we performed studies aimed at identifying non-steroidal ligands for this motif. Molecular modeling and in silico screening of large chemical libraries identified a panel of compounds which were subsequently screened for bioactivity in a number of steroidogenic model systems. These efforts identified a family of non-steroidal CRAC ligands able to potently inhibit steroidogenesis, and at higher concentrations, promote apoptosis. In addition, the best candidate in this family was able to suppress testosterone synthesis when administered to rats, indicating that this novel family of non-steroidal CRAC ligands may serve as prototypes for the development of drugs useful for treatment of diseases of steroid overproduction, such as Cushing's syndrome and steroidogenic cell tumors in humans and animals.
线粒体在细胞的生理稳态中发挥着关键作用，参与众多细胞过程，包括生物能量学、新陈代谢以及细胞的生死存亡。由于其关键作用，线粒体作为药理学靶点备受关注。线粒体外膜整合转运蛋白（TSPO）因其能够以高亲和力和特异性结合多种药物而引起了极大的药理学兴趣。除了其特征明确的药物结合位点外，TSPO还拥有一个额外的高亲和力配体结合位点，最初因其能够结合脂质胆固醇而被鉴定出来，该位点被命名为胆固醇识别/相互作用氨基酸共识（CRAC）基序。我们实验室之前的研究确定了靶向TSPO的CRAC基序的其他配体，这些配体能够有效抑制线粒体胆固醇转运和类固醇生物合成，而TSPO在这些过程中已有充分的特征描述。然而，所有这些化合物都具有胆固醇和类固醇激素共有的甾体骨架。为了进一步了解TSPO的CRAC基序，我们进行了旨在鉴定该基序非甾体配体的研究。通过对大型化学文库进行分子建模和计算机筛选，确定了一组化合物，随后在多个类固醇生成模型系统中对其生物活性进行了筛选。这些研究确定了一类能够有效抑制类固醇生成的非甾体CRAC配体，在较高浓度下还能促进细胞凋亡。此外，该家族中最佳候选物在给大鼠给药时能够抑制睾酮合成，这表明这一新的非甾体CRAC配体家族可能成为开发用于治疗类固醇过度分泌疾病（如人类和动物的库欣综合征和类固醇生成细胞瘤）药物的原型。
