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Abstract：
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.
摘要：
线粒体在细胞的生理稳态中起着关键作用，有助于许多细胞过程，包括生物能学，新陈代谢和细胞生与死。由于他们的基石作用，线粒体作为药理靶点受到了广泛的关注。外部线粒体整合膜转运蛋白（TSPO）由于其能够以高亲和力和特异性结合许多类别的药物而引起了很大程度的药理学兴趣。除了其特征明确的药物结合位点，TSPO具有额外的高亲和力配体结合位点，最初被确定为具有结合脂质胆固醇的能力，其被命名为胆固醇识别/相互作用氨基酸共有(CRAC)基序。我们实验室先前的研究发现了针对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。TSPO已被很好地表征的过程。然而,所有这些化合物都具有胆固醇和类固醇激素常见的甾体骨架。在我们努力扩大对TSPO的CRAC主题的理解时，我们进行了旨在确定该基序的非甾体配体的研究。分子建模和大型化学文库的计算机筛选鉴定了一组化合物，随后在许多类固醇生成模型系统中对其进行了生物活性筛选。这些努力确定了能够有效抑制类固醇生成的非甾体CRAC配体家族，在更高的浓度下，促进细胞凋亡。此外,这个家族中最好的候选人在给大鼠服用时能够抑制睾酮合成，这表明这种新型的非甾体CRAC配体家族可以作为开发用于治疗类固醇过度生产疾病的药物的原型，如人类和动物的库欣综合征和类固醇细胞肿瘤。
