Alleviation of oxidative stress by potent and selective thioredoxin-mimetic peptides
Alleviation of oxidative stress by potent and selective thioredoxin-mimetic peptides
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DOI：
10.1016/j.freeradbiomed.2011.02.026
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发表时间：
2011-05-15
影响因子：
7.4
通讯作者：
Atlas, Daphne
中科院分区：
文献类型：
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作者：
Bachnoff, Niv;Trus, Michael;Atlas, Daphne
TrxR-Trx 系统是提供氧化损伤保护的主要酶细胞防御系统之一。它由 NADPH 和硫氧还蛋白还原酶 (TrxR) 组成，可维持硫氧还蛋白 (Trx) 处于还原状态。用选择性 TrxR 抑制剂金诺芬（AuF；2,3,4,6-四-O-乙酰基-1-硫代-β-D-吡喃葡萄糖基-S-（三乙基膦）金）干扰 TrxR-Trx 系统，通过使 Trx 保持氧化状态来诱导氧化应激。我们制备了一系列源自 Trx 活性位点的典型 CxxC 基序和修饰的 CxC 基序的三寡肽和四寡肽家族。这些 Trx 模拟化合物是 N 端和 C 端封闭的肽，由位于两个氨基酸 CxxC 基序（CM 和 CB6）或单氨基酸 CxC 基序（CB3）侧翼的两个半胱氨酸残基组成。 AuF 消除了牛嗜铬细胞中儿茶酚胺 (CA) 的分泌，这是一个高度氧化还原敏感的过程。通过单细胞电流分析法监测，Trx 模拟肽有效恢复 CA 分泌。它们还可以防止 AuF 诱导的 p38 丝裂原激活蛋白激酶 (MAPK) 和 c-Jun NH2 末端激酶的磷酸化。在 PC12 细胞中，Trx 样肽减轻 AuF 诱导的 ERK1/2-MAPK 磷酸化与其恢复 CA 分泌的作用平行。 CB3、CB4 和 CB6 在细胞内发挥作用，比传统抗氧化剂 NAC、GSH、DTT、AD4（NAC-酰胺）和抗坏血酸更有效。总而言之，CxxC 和 CxC 肽代表了一个新的有效和选择性氧化还原化合物家族，可以作为预防和治疗氧化应激相关疾病的潜在候选化合物。 (C) 2011 Elsevier Inc. 保留所有权利。
One of the major enzymatic cell defenses providing protection from oxidative injury is the TrxR-Trx system. It consists of NADPH and thioredoxin reductase (TrxR), which maintain thioredoxin (Trx) in a reduced state. Perturbing the TrxR-Trx system with the selective TrxR inhibitor auranofin (AuF; 2,3,4,6-tetra-O-acetyl-1-thio-beta-D-glucopyranosato-S-(triethylphosphine) gold) induces oxidative stress by keeping Trx in its oxidized state. We have prepared a family of tri- and tetra-oligopeptides derived from the canonical CxxC motif of the Trx active site and a modified CxC motif. These Trx-mimetic compounds are N- and C-terminal-blocked peptides that consist of two cysteine residues that flank the two-amino-acid CxxC motif (CM and CB6) or the single-amino-acid CxC motif (CB3). Catecholamine (CA) secretion in bovine chromaffin cells, which is a highly redox sensitive process, is abolished by AuF. The Trx-mimetic peptides effectively restore CA secretion, as monitored by amperometry in single cells. They also prevent the AuF-induced phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase. In PC12 cells, the alleviation of AuF-induced ERK1/2-MAPK phosphorylation by Trx-like peptides parallels their effect of restoring CA secretion. CB3, CB4, and CB6 act intracellularly and are significantly more potent than the traditional antioxidants NAC, GSH, DTT, AD4 (NAC-amide), and ascorbic acid. Taken together, the CxxC and CxC peptides represent a new family of potent and selective redox compounds that could serve as potential candidates for prevention and treatment of oxidative-stress-related disorders. (C) 2011 Elsevier Inc. All rights reserved.