{
  "abstract": "Alzheimer’s disease (AD) is driven primarily by the self-assembly of amyloid-β (Aβ) peptides, a process stabilized by intermolecular π–π stacking interactions involving Phe19 and Phe20 residues of adjacent Aβ molecules. To competitively disrupt these interactions, we designed novel peptide inhibitors derived from the Aβ recognition motif KLVFFA (Aβ16–21), in which phenylalanine residues were replaced with L-3,4-dihydroxyphenylalanine (DOPA), featuring a catechol moiety capable of enhanced aromatic stacking and hydrogen bonding. The DOPA-substituted peptides effectively inhibited Aβ1–42 (Aβ42) aggregation, as demonstrated via Thioflavin T fluorescence assays, circular dichroism spectroscopy, and transmission electron microscopy. These complementary analyses collectively revealed substantial suppression of β-sheet formation and fibril elongation. Notably, the anti-aggregation potency was dependent on the substitution position, with the Phe19-substituted analog (KDF) exhibiting stronger inhibitory activity than the Phe20-substituted analog (KFD). The dual-substituted analog (KDD) displayed the greatest overall anti-aggregation activity. Molecular simulations further supported the superior activity of KDF over KFD, revealing a more favorable binding free energy for KDF compared to the parent peptide. Furthermore, the DOPA peptides potently mitigated Aβ42-induced neurotoxicity in SH−SY5Y cells, with the dual-substituted analog (KDD) providing the highest level of cytoprotection. Collectively, these findings validate that targeted modulation of aromatic interactions through DOPA substitution represents a powerful molecular strategy for controlling Aβ42 self-assembly, positioning these peptides as promising therapeutic tools for the treatment of AD.",
  "abstract_shown": true,
  "affiliations": [
    "Division of Organic and Medicinal Chemistry, Department of Pharmaceutical Sciences, School of Pharmacy, Showa Medical University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan",
    "Division of Cancer Cell Biology, Department of Pharmaceutical Sciences, School of Pharmacy, Showa Medical University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan",
    "Division of Biological Chemistry, Department of Pharmaceutical Sciences, School of Pharmacy, Showa Medical University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan",
    "Graduate School of Human Development and Environment, Kobe University, 3-11 Tsurukabuto, Nada-ku, Kobe 657-8501, Japan",
    "Center for Electron Microscopy, Showa Medical University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan",
    "Division of Organic Chemistry, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki City 210-9501, Japan",
    "Division of Drugs, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki City 210-9501, Japan",
    "Division of Genome Safety Science, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki City 210-9501, Japan"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Kiyoshi Fukuhara",
      "orcid": "0000-0001-9677-7911"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Kazunori Mori"
    },
    {
      "affs": [
        3
      ],
      "name": "Yoshio Okiyama",
      "orcid": "0000-0002-6775-8604"
    },
    {
      "affs": [
        4
      ],
      "name": "Takashi Takaki"
    },
    {
      "affs": [
        5
      ],
      "name": "Takashi Misawa"
    },
    {
      "affs": [
        6
      ],
      "name": "Keisuke Tsuchiya"
    },
    {
      "affs": [
        5
      ],
      "name": "Yosuke Demizu",
      "orcid": "0000-0001-7521-4861"
    },
    {
      "affs": [
        1
      ],
      "name": "Motoko Shibanuma",
      "orcid": "0000-0002-8726-8047"
    },
    {
      "affs": [
        7
      ],
      "name": "Akiko Ohno",
      "orcid": "0000-0002-0109-2707"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/af69e6gt580n9.bib",
  "cited_by": 0,
  "doi": "10.3390/ijms27219503",
  "fulltext_url": null,
  "id": "af69e6gt580n9",
  "issns": [
    "1422-0067"
  ],
  "landing_url": "https://www.mdpi.com/1422-0067/27/21/9503",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2737|Alzheimer's disease research and treatments"
    ]
  ],
  "openalex": "W7223846671",
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-24",
  "publisher": "MDPI AG",
  "ris": "https://research.draconitic.com/paper/af69e6gt580n9.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:57Z",
      "native_id": "10.3390/ijms27219503",
      "source": "crossref",
      "url": "https://www.mdpi.com/1422-0067/27/21/9503"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2737|Alzheimer's disease research and treatments",
      "subfield": "physiology"
    }
  ],
  "title": "DOPA-Substituted KLVFFA Peptides Potently Inhibit Amyloid-β Aggregation and Mitigate Neurotoxicity",
  "title_text": "DOPA-Substituted KLVFFA Peptides Potently Inhibit Amyloid-β Aggregation and Mitigate Neurotoxicity",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:18:57Z",
  "url": "https://research.draconitic.com/paper/af69e6gt580n9",
  "venue": "International Journal of Molecular Sciences",
  "versions": []
}