Fluorescent Peptides Sequester Redox Copper to Mitigate Oxidative Stress, Amyloid Toxicity, and Neuroinflammation

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-07-25 DOI:10.1021/acsmedchemlett.4c00283

Sabyasachi Mandal, Yelisetty Venkata Suseela, Sourav Samanta, Bertrand Vileno, Peter Faller, Thimmaiah Govindaraju

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Abstract

Alzheimer’s disease is a progressive neurodegenerative disorder that significantly contributes to dementia. The lack of effective therapeutic interventions presents a significant challenge to global health. We have developed a set of short peptides (PN_Gln) conjugated with a dual-functional fluorophoric amino acid (N_Gln). The lead peptide, P2N_Gln, displays a high affinity for Cu²⁺, maintaining the metal ion in a redox-inactive state. This mitigates the cytotoxicity generated by reactive oxygen species (ROS), which are produced by Cu²⁺ under the reductive conditions of Asc and Aβ₁₆ or Aβ₄₂. Furthermore, P2N_Gln inhibits both Cu-dependent and -independent fibrillation of Aβ₄₂, along with the subsequent toxicity induced by Aβ₄₂. In addition, P2N_Gln exhibits inhibitory effects on the production of lipopolysaccharide (LPS)-induced ROS and reactive nitrogen species (RNS) in microglial cells. In vitro and cellular studies indicate that P2N_Gln could significantly reduce Aβ–Cu²⁺-induced ROS production, amyloid toxicity, and neuroinflammation, offering an innovative strategy against Alzheimer’s disease.

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荧光肽螯合氧化还原铜，缓解氧化应激、淀粉样蛋白毒性和神经炎症

阿尔茨海默病是一种渐进性神经退行性疾病，是导致痴呆症的重要原因。缺乏有效的治疗干预对全球健康构成了重大挑战。我们开发了一组与双功能含氟氨基酸（NGln）共轭的短肽（PNGln）。主肽 P2NGln 对 Cu2+ 具有高亲和力，能使金属离子保持氧化还原不活跃状态。这减轻了活性氧（ROS）产生的细胞毒性，ROS 是 Cu2+ 在 Asc 和 Aβ16 或 Aβ42 的还原条件下产生的。此外，P2NGln 还能抑制 Aβ42 依赖 Cu 和不依赖 Cu 的纤维化，以及随后由 Aβ42 引发的毒性。此外，P2NGln 还能抑制小胶质细胞中脂多糖（LPS）诱导的 ROS 和活性氮物种（RNS）的产生。体外和细胞研究表明，P2NGln 能显著减少 Aβ-Cu2+ 诱导的 ROS 生成、淀粉样蛋白毒性和神经炎症，为防治阿尔茨海默病提供了一种创新策略。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.

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