Department of Microbiology & Immunology, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China.
BMC Complement Altern Med. 2014 Oct 15;14:400. doi: 10.1186/1472-6882-14-400.
The Mycobacterium tuberculosis (Mtb) proteasome has been established as a viable target for the development of anti-tuberculosis agents. In this study, the inhibitory activities of 100 plant-derived natural products on the Mtb proteasome were analyzed to identify novel potential inhibitors.
The fluorescent substrate Suc-Leu-Leu-Val-Tyr-AMC can be hydrolyzed by the proteasome to release free AMC, the fluorescence of which is proportional to the proteasome activity. The inhibitory activities of 100 natural products (each at a final concentration of 200 μM) were detected by this method using MG132 as a positive control.
Twelve of these natural products (10 of which were flavonoids) inhibited the activity of the Mtb proteasome by more than 65%. Comparison of the structural differences between the flavonoids with good inhibitory activity and those without inhibitory activity revealed that the hydroxyl at the flavonoid C ring C-3 or the hydroxyl/methoxyl at the flavonoid A ring C-6 were critical for the inhibition of proteasomal activity.
These data indicate that flavonoids represent a basis for rational structural design in the process of novel anti-tuberculosis drug discovery.
结核分枝杆菌（Mtb）蛋白酶体已被确定为开发抗结核药物的可行靶点。在这项研究中，分析了 100 种植物来源的天然产物对 Mtb 蛋白酶体的抑制活性，以鉴定新的潜在抑制剂。
荧光底物 Suc-Leu-Leu-Val-Tyr-AMC 可被蛋白酶体水解，释放出游离的 AMC，其荧光与蛋白酶体活性成正比。使用 MG132 作为阳性对照，通过该方法检测 100 种天然产物（每种终浓度为 200 μM）的抑制活性。
其中 12 种天然产物（其中 10 种为黄酮类化合物）对 Mtb 蛋白酶体的活性抑制超过 65%。对具有良好抑制活性的黄酮类化合物和无抑制活性的黄酮类化合物之间的结构差异进行比较，发现黄酮类化合物 C 环 C-3 位的羟基或 A 环 C-6 位的羟基/甲氧基对抑制蛋白酶体活性至关重要。
这些数据表明，黄酮类化合物代表了在新型抗结核药物发现过程中进行合理结构设计的基础。
