{"title":"Fluorescent Peptides Sequester Redox Copper to Mitigate Oxidative Stress, Amyloid Toxicity, and Neuroinflammation","authors":"Sabyasachi Mandal, Yelisetty Venkata Suseela, Sourav Samanta, Bertrand Vileno, Peter Faller, Thimmaiah Govindaraju","doi":"10.1021/acsmedchemlett.4c00283","DOIUrl":null,"url":null,"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<sub>Gln</sub>) conjugated with a dual-functional fluorophoric amino acid (N<sub>Gln</sub>). The lead peptide, P2N<sub>Gln</sub>, displays a high affinity for Cu<sup>2+</sup>, maintaining the metal ion in a redox-inactive state. This mitigates the cytotoxicity generated by reactive oxygen species (ROS), which are produced by Cu<sup>2+</sup> under the reductive conditions of Asc and Aβ<sub>16</sub> or Aβ<sub>42</sub>. Furthermore, P2N<sub>Gln</sub> inhibits both Cu-dependent and -independent fibrillation of Aβ<sub>42</sub>, along with the subsequent toxicity induced by Aβ<sub>42</sub>. In addition, P2N<sub>Gln</sub> 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<sub>Gln</sub> could significantly reduce Aβ–Cu<sup>2+</sup>-induced ROS production, amyloid toxicity, and neuroinflammation, offering an innovative strategy against Alzheimer’s disease.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":3.5000,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Medicinal Chemistry Letters","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acsmedchemlett.4c00283","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
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 (PNGln) conjugated with a dual-functional fluorophoric amino acid (NGln). The lead peptide, P2NGln, 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, P2NGln inhibits both Cu-dependent and -independent fibrillation of Aβ42, along with the subsequent toxicity induced by Aβ42. In addition, P2NGln 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 P2NGln could significantly reduce Aβ–Cu2+-induced ROS production, amyloid toxicity, and neuroinflammation, offering an innovative strategy against Alzheimer’s disease.
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.