Natural products triptolide, celastrol, and withaferin A inhibit the chaperone activity of peroxiredoxin I

Abstract

The natural products triptolide, withaferin A and celastrol have been discovered to be novel Prx I chaperone inhibitors using synthetic chemical probes.

A Mechanistic Overview of Triptolide and Celastrol, Natural Products from Tripterygium wilfordii Hook F

“…Triptolide binds to the cysteine residues of target proteins through covalent bond; and thus modifies the properties and activities of the target proteins. However, no epoxide moiety is observed on other TWHF compounds such as withaferin A and celastrol, although they exhibits the same activities as triptolide ( Zhao Q. et al, 2015 ). In withaferin A and celastrol, 1,4-dipolar structure constructed by the carbonyl and adjacent double carbon-carbon bond that binds to the cysteine residues of the target proteins.…”

“…Results from molecular docking and dynamics simulation study suggest that triptolide has similar structures as hormones and thus can also bind to nuclear receptors ( Liu X. et al, 2015 ). Triptolide selectively inhibits the chaperone activity of peroxiredoxin I, an antioxidant enzyme and molecular chaperone that plays essential functions in the development of cancer and inflammation ( Zhao Q. et al, 2015 ). The XBP1 subunit of the transcription factor TFIIH core complex is identified as one of the molecular targets of triptolide, which was critical for the inhibitory activity of triptolide to RNA polymerase II-mediated transcription ( Titov et al, 2011 ).…”

“…Inspired by the epoxide’s effect on protein proposed by Zhao Q. et al (2015) , the epoxide moieties on the C-6a and C-7a positions of triptolide could act as acceptors for cysteine ( Figure 1 ). Triptolide directly binds to cysteine via the ring-opening interaction between epoxide and -SH moiety of cysteine, which could lead to the dissociation of these proteins to their downstream target elements.…”

Target Identification of Bioactive Natural Products

“…早在 20 世纪 90 年代, 哈佛大学 Schreiber 团队 [12] 利用固 载小分子的亲和层析方法在小牛胸腺和人脾细胞裂解 液 中分 离出了 天然 免疫抑 制 剂 FK506 的结 合蛋白 FKBP12 及其复合物, 并发现了环肽天然产物 Trapoxin 与组蛋白去乙酰化酶(HDAC)的特异性结合 [13] . 另外一 [20] , 腺 花 素 (Adenanthin) [28] , 雷 公 藤 甲 素 (Triptolide) [29] 和 黄 连 素 (Berberine) [30] 等. 时至今日, 这种最为直接的亲和层析 方法仍然在靶标鉴定领域得到广泛应用.…”

“…Oleocanthal [23] Artemisinin [26] Withaferin A [20] Celastrol [25] Triptolide [29] Eriocalyxin B [27] Adenanthin [28] Pateamine A [18] Radicicol [21] [37] , 胆 固 醇 (Cholesterol) [38] , 羟 基 德 里 辛 (4-Hydroxyderricin) [39] , 阿西维辛(Acivicin) [40] , 姜黄素 (Curcumin) [41] , 穿心莲内酯(Andrographolide) [42] 以及青 蒿素(Artemisinin) [43] 等. 图 3 列举了近年来具有代表性 的利用生物正交反应基团进行衍生化的天然产物探针 实例 [37～51] .…”