Department of Chemical Engineering, Stanford University , Stanford, California 94305, USA.
J Med Chem. 2013 Feb 14;56(3):1301-10. doi: 10.1021/jm301775s. Epub 2013 Jan 31.
Whereas the role of mammalian thioredoxin (Trx) as an intracellular protein cofactor is widely appreciated, its function in the extracellular environment is not well-understood. Only few extracellular targets of Trx-mediated thiol-disulfide exchange are known. For example, Trx activates extracellular transglutaminase 2 (TG2) via reduction of an intramolecular disulfide bond. Because hyperactive TG2 is thought to play a role in various diseases, understanding the biological role of extracellular Trx may provide critical insight into the pathogenesis of these disorders. Starting from a clinical-stage asymmetric disulfide lead, we have identified analogs with >100-fold specificity for Trx. Structure-activity relationship and computational docking model analyses have provided insights into the features important for enhancing potency and specificity. The most active compound identified had an IC(50) below 0.1 μM in cell culture and may be appropriate for in vivo use to interrogate the role of extracellular Trx in health and disease.
尽管哺乳动物硫氧还蛋白 (Trx) 作为细胞内蛋白辅因子的作用已被广泛认识，但它在细胞外环境中的功能却知之甚少。已知只有少数 Trx 介导的巯基-二硫键交换的细胞外靶标。例如，Trx 通过还原分子内二硫键来激活细胞外转谷氨酰胺酶 2 (TG2)。由于高活性的 TG2 被认为在各种疾病中发挥作用，因此了解细胞外 Trx 的生物学作用可能为这些疾病的发病机制提供重要的见解。从一个临床阶段的不对称二硫键先导化合物开始，我们已经鉴定出对 Trx 具有 >100 倍特异性的类似物。结构-活性关系和计算对接模型分析提供了增强效力和特异性的重要特征的见解。鉴定出的最活跃的化合物在细胞培养中的 IC(50)低于 0.1 μM，可能适合于体内使用，以研究细胞外 Trx 在健康和疾病中的作用。
