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Peer-reviewedCC BY 4.0International Journal of Molecular Sciences

DOPA-Substituted KLVFFA Peptides Potently Inhibit Amyloid-β Aggregation and Mitigate Neurotoxicity

  • Kiyoshi Fukuhara1
  • Kazunori Mori2,3
  • Yoshio Okiyama4
  • Takashi Takaki5
  • Takashi Misawa6
  • Keisuke Tsuchiya7
  • Yosuke Demizu6
  • Motoko Shibanuma2
  • Akiko Ohno8
8 affiliations
  1. 1Division 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
  2. 2Division of Cancer Cell Biology, Department of Pharmaceutical Sciences, School of Pharmacy, Showa Medical University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
  3. 3Division of Biological Chemistry, Department of Pharmaceutical Sciences, School of Pharmacy, Showa Medical University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
  4. 4Graduate School of Human Development and Environment, Kobe University, 3-11 Tsurukabuto, Nada-ku, Kobe 657-8501, Japan
  5. 5Center for Electron Microscopy, Showa Medical University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
  6. 6Division of Organic Chemistry, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki City 210-9501, Japan
  7. 7Division of Drugs, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki City 210-9501, Japan
  8. 8Division of Genome Safety Science, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki City 210-9501, Japan
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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.

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Cite

BibTeXRIS
BibTeX
@article{fukuhara2026dopasubstituted,
  title = {{DOPA-Substituted KLVFFA Peptides Potently Inhibit Amyloid-β Aggregation and Mitigate Neurotoxicity}},
  author = {Kiyoshi Fukuhara and Kazunori Mori and Yoshio Okiyama and Takashi Takaki and Takashi Misawa and Keisuke Tsuchiya and Yosuke Demizu and Motoko Shibanuma and Akiko Ohno},
  journal = {International Journal of Molecular Sciences},
  year = {2026},
  month = oct,
  doi = {10.3390/ijms27219503},
  url = {https://www.mdpi.com/1422-0067/27/21/9503},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - DOPA-Substituted KLVFFA Peptides Potently Inhibit Amyloid-β Aggregation and Mitigate Neurotoxicity
AU  - Kiyoshi Fukuhara
AU  - Kazunori Mori
AU  - Yoshio Okiyama
AU  - Takashi Takaki
AU  - Takashi Misawa
AU  - Keisuke Tsuchiya
AU  - Yosuke Demizu
AU  - Motoko Shibanuma
AU  - Akiko Ohno
PY  - 2026
DA  - 2026/10/24
JO  - International Journal of Molecular Sciences
DO  - 10.3390/ijms27219503
UR  - https://www.mdpi.com/1422-0067/27/21/9503
AB  - 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.
SN  - 1422-0067
ER  -