Gencheva Radosveta, Cheng Qing, Arnér Elias S J
Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, 17177, Sweden.
Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, 17177, Sweden; Department of Selenoprotein Research, National Tumor Biology Laboratory, National Institute of Oncology, 1122, Budapest, Hungary.
Free Radic Biol Med. 2022 Sep;190:320-338. doi: 10.1016/j.freeradbiomed.2022.07.020. Epub 2022 Aug 17.
Human thioredoxin reductase (TrxR) is a selenoprotein with a central role in cellular redox homeostasis, utilizing a highly reactive and solvent-exposed selenocysteine (Sec) residue in its active site. Pharmacological modulation of TrxR can be obtained with several classes of small compounds showing different mechanisms of action, but most often dependent upon interactions with its Sec residue. The clinical implications of TrxR modulation as mediated by small compounds have been studied in diverse diseases, from rheumatoid arthritis and ischemia to cancer and parasitic infections. The possible involvement of TrxR in these diseases was in some cases serendipitously discovered, by finding that existing clinically used drugs are also TrxR inhibitors. Inhibiting isoforms of human TrxR is, however, not the only strategy for human disease treatment, as some pathogenic parasites also depend upon Sec-containing TrxR variants, including S. mansoni, B. malayi or O. volvulus. Inhibiting parasite TrxR has been shown to selectively kill parasites and can thus become a promising treatment strategy, especially in the context of quickly emerging resistance towards other drugs. Here we have summarized the basis for the targeting of selenoprotein TrxR variants with small molecules for therapeutic purposes in different human disease contexts. We discuss how Sec engagement appears to be an indispensable part of treatment efficacy and how some therapeutically promising compounds have been evaluated in preclinical or clinical studies. Several research questions remain before a wider application of selenoprotein TrxR inhibition as a first-line treatment strategy might be developed. These include further mechanistic studies of downstream effects that may mediate treatment efficacy, identification of isoform-specific enzyme inhibition patterns for some given therapeutic compounds, and the further elucidation of cell-specific effects in disease contexts such as in the tumor microenvironment or in host-parasite interactions, and which of these effects may be dependent upon the specific targeting of Sec in distinct TrxR isoforms.
人硫氧还蛋白还原酶（TrxR）是一种硒蛋白，在细胞氧化还原稳态中起核心作用，其活性位点含有一个高度反应性且暴露于溶剂中的硒代半胱氨酸（Sec）残基。TrxR的药理学调节可通过几类具有不同作用机制的小分子化合物实现，但大多数情况下取决于与Sec残基的相互作用。小分子介导的TrxR调节在多种疾病中的临床意义已得到研究，从类风湿性关节炎、局部缺血到癌症和寄生虫感染。在某些情况下，通过发现现有的临床使用药物也是TrxR抑制剂，偶然发现了TrxR可能参与这些疾病。然而，抑制人TrxR的亚型并非人类疾病治疗的唯一策略，因为一些致病寄生虫也依赖含Sec的TrxR变体，包括曼氏血吸虫、马来布鲁线虫或盘尾丝虫。抑制寄生虫TrxR已被证明可选择性杀死寄生虫，因此可能成为一种有前景的治疗策略，特别是在对其他药物迅速产生耐药性的情况下。在此，我们总结了在不同人类疾病背景下，利用小分子靶向硒蛋白TrxR变体用于治疗目的的依据。我们讨论了Sec参与似乎是治疗效果不可或缺的一部分，以及一些具有治疗前景的化合物在临床前或临床研究中的评估情况。在将硒蛋白TrxR抑制作为一线治疗策略更广泛应用之前，仍有几个研究问题有待解决。这些问题包括对可能介导治疗效果的下游效应进行进一步的机制研究，确定某些特定治疗化合物的亚型特异性酶抑制模式，以及进一步阐明疾病背景下的细胞特异性效应，如肿瘤微环境或宿主 - 寄生虫相互作用中的效应，以及这些效应中哪些可能依赖于不同TrxR亚型中Sec的特异性靶向。
