Natural Tripeptide-Based Inhibitor of Multifaceted Amyloid β Toxicity
Natural Tripeptide-Based Inhibitor of Multifaceted Amyloid β Toxicity
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DOI：
10.1021/acschemneuro.6b00175
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发表时间：
2016-09-01
影响因子：
5
通讯作者：
Govindaraju, T.
中科院分区：
文献类型：
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作者：
Rajasekhar, K.;Madhu, Chilakapati;Govindaraju, T.
β 淀粉样蛋白 (Aβ) 肽及其聚集物在人脑中的积累被认为是阿尔茨海默病 (AD) 的标志之一。 Aβ 的多态性寡聚物和完全生长的纤维状聚集体表现出不同程度的神经元毒性。此外，在存在氧化还原活性金属离子（如 Cu2+）的情况下，Aβ 的聚集是由活性氧（ROS）的产生引起的细胞毒性的额外特征的原因。在此，基于天然存在的金属螯合三肽（GHK）和 Aβ 聚集抑制剂，提出了一种多功能拟肽抑制剂（P6）。通过各种生物物理学研究表明，P6 与 Aβ 相互作用，并防止形成有毒的 Aβ 形式，如寡聚物和纤维状聚集体。此外，P6 成功地从 A beta-Cu2+ 复合物中螯合 Cu2+，并将其维持在氧化还原休眠状态，以防止 ROS 的产生。 P6 抑制 A β 寡聚物造成的膜破坏，并有效防止 A β-Cu2+ 复合物引起的 DNA 损伤。当用 P6 处理时，PC12 细胞免于多方面的 Aβ 毒性，并且细胞中产生的 ROS 量减少。这些特性使 P6 成为改善 AD 多方面 A 毒性的潜在治疗候选药物。
Accumulation of amyloid beta (A beta) peptide and its aggregates in the human brain is considered as one of the hallmarks of Alzheimer's disease (AD). The polymorphic oligomers and fully grown fibrilar aggregates of A beta exhibit different levels of neuronal toxicity. Moreover, aggregation of A beta in the presence of redox-active metal ions like Cu2+ is responsible for the additional trait of cellular toxicity induced by the generation of reactive oxygen species (ROS). Herein, a multifunctional peptidomimetic inhibitor (P6) has been presented, based on a naturally occurring metal chelating tripeptide (GHK) and the inhibitor of A beta aggregation. It was shown by employing various biophysical studies that P6 interact with A beta and prevent the formation of toxic A beta forms like oligomeric species and fibrillar aggregates. Further, P6 successfully sequestered Cu2+ from the A beta-Cu2+ complex and maintained it in a redox-dormant state to prevent the generation of ROS. P6 inhibited membrane disruption by A beta oligomers and efficiently prevented DNA damage caused by the A beta-Cu2+ complex. PC12 cells were rescued from multifaceted A beta toxicity when treated with P6, and the amount of ROS generated in cells was reduced. These attributes make P6 a potential therapeutic candidate to ameliorate the multifaceted A toxicity in AD.