University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000 Ljubljana, Slovenia.
Department of Medicinal Chemistry, University of Minnesota, 308 Harvard Street Southeast, Minneapolis, MN 55455, USA.
Molecules. 2020 Mar 12;25(6):1305. doi: 10.3390/molecules25061305.
Protein degradation is a fundamental process in all living organisms. An important part of this system is a multisubunit, barrel-shaped protease complex called the proteasome. This enzyme is directly responsible for the proteolysis of ubiquitin- or pup-tagged proteins to smaller peptides. In this study, we present a series of 92 psoralen derivatives, of which 15 displayed inhibitory potency against the proteasome in low micromolar concentrations. The best inhibitors, i.e., , , and , exhibited a mixed type of inhibition and overall good inhibitory potency in biochemical assays. -(cyanomethyl)acetamide ( = 5.6 µM) and carboxaldehyde-based derivative ( = 14.9 µM) were shown to be reversible inhibitors of the enzyme. On the other hand, pyrrolidine-2,5-dione esters and irreversibly inhibited the enzyme with values of 4.2 µM and 1.1 µM, respectively. In addition, we showed that an established immunoproteasome inhibitor, , is a noncompetitive irreversible inhibitor of the mycobacterial proteasome ( = 5.2 ± 1.9 µM, / = 96 ± 41 M·s). These compounds represent interesting hit compounds for further optimization in the development of new drugs for the treatment of tuberculosis.
蛋白质降解是所有生物体的基本过程。该系统的一个重要部分是多亚基、桶形蛋白酶复合物，称为蛋白酶体。这种酶直接负责将泛素或 pup 标记的蛋白质降解为较小的肽。在这项研究中，我们提供了一系列 92 种补骨脂素衍生物，其中 15 种在低微摩尔浓度下显示出对蛋白酶体的抑制活性。最好的抑制剂，即 、 、 和 ，在生化测定中表现出混合抑制类型和整体良好的抑制活性。-(氰甲基)乙酰胺（ = 5.6 µM）和基于醛的衍生物 （ = 14.9 µM）被证明是酶的可逆抑制剂。另一方面，吡咯烷-2,5-二酮酯 和 分别以 4.2 µM 和 1.1 µM 的 值不可逆地抑制了酶。此外，我们表明，一种已建立的免疫蛋白酶体抑制剂 ，是非竞争性不可逆抑制剂（ = 5.2 ± 1.9 µM，/ = 96 ± 41 M·s）。这些化合物代表了有趣的命中化合物，可进一步优化开发用于治疗结核病的新药。
