A Boronic Acid Conjugate of Angiogenin that Shows ROS-Responsive Neuroprotective Activity.
A Boronic Acid Conjugate of Angiogenin that Shows ROS-Responsive Neuroprotective Activity.
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DOI：
10.1002/anie.201611446
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发表时间：
2017-03-01
期刊：
影响因子：
--
通讯作者：
Raines RT
中科院分区：
文献类型：
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作者：
Hoang TT;Smith TP;Raines RT
血管生成素（ANG）是一种在肌萎缩侧索硬化症（ALS）患者中受损的人核糖核酸酶。ANG还促进新血管形成，并可诱导出血和促进肿瘤生长。ALS的病因性神经变性与活性氧物质有关，活性氧物质也已知引起碳-硼键的氧化裂解。我们已经开发了一种合成硼酸掩模，抑制ANG的核糖核酸溶解活性。被掩蔽的ANG不刺激内皮细胞增殖，但保护星形胶质细胞免受氧化应激。通过区分ANG的两种二分生物活性，该策略预示了治疗ALS的可行药理学方法。蛋白质功能的时空控制可以导致新的治疗方式。血管生成素在ALS患者中受损。半合成的血管生成素有一个关键的活性位点残基，被硼酸掩盖，破坏了有害的副作用。过氧化氢与肌萎缩侧索硬化症有关，它会揭开血管生成素的面纱，然后保护星形胶质细胞。
Angiogenin (ANG) is a human ribonuclease that is compromised in patients with amyotrophic lateral sclerosis (ALS). ANG also promotes neovascularization, and can induce hemorrhage and encourage tumor growth. The causal neurodegeneration of ALS is associated with reactive oxygen species, which are also known to elicit the oxidative cleavage of carbon–boron bonds. We have developed a synthetic boronic acid mask that restrains the ribonucleolytic activity of ANG. The masked ANG does not stimulate endothelial cell proliferation but protects astrocytes from oxidative stress. By differentiating between the two dichotomous biological activities of ANG, this strategy predicates a viable pharmacological approach for the treatment of ALS. Spatiotemporal control of protein function can lead to new therapeutic modalities. Angiogenin is damaged in ALS patients. A semisynthetic angiogenin has a key active-site residue masked with a boronic acid, vitiating deleterious side effects. Hydrogen peroxide, which is linked to ALS, unmasks the angiogenin, which then protects astroglia.