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Purpose <p>Parkinson’s disease (PD), the second most frequently occurring neurodegenerative disorder. Alpha-synuclein, the principal protein found in Lewy bodies, plays a central role in the disease process of PD. Emerging biochemical and genetic data suggest that the formation of alpha-synuclein inclusion bodies is an early event in disease pathogenesis and is also common to demential with Lewy bodies and multiple system atrophy. This study sought to identify and characterize peptide inhibitors of alpha-synuclein fibrillation as a potential therapeutic strategy.</p> Methods <p>The structural and sequence basis for inhibiting alpha-synuclein fibrillation was analyzed from the PDB database concentrating on the residues 60–70 of the NAC region. A six-amino-acid peptide library was designed containing point mutations within that hydrophilic domain, and the most hydrophilic variants were screened by ToxinPred, AlgPred, CPP, BBB, and Haddock servers. Molecular dynamics simulations (100 ns) were performed using GROMACS to assess peptide stability and binding energy. The most suggestive peptide was synthesized using solid-phase synthesis (SPPS), purified using HPLC, and characterized using LC–MS. Fibril inhibition was assessed using thioflavin T (ThT) fluorescence assays, and cell viability was determined with MTT assays using SH-SY5Y cells.</p> Results <p>The peptide KEQPTN made the best inhibit alpha-synuclein fibrillation due to its proline residue, enhancing hydrophilicity and thereby preventing aggregation. The in vitro assays confirmed modest fibril reduction with low cytotoxicity, suggesting therapeutic potential.</p> Conclusion <p>The peptide brings with it the breath of hope against alpha-synuclein aggregation, a plausible strategy to curb PD. Further studies would be warranted.</p>

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Development of a Peptide Inhibitor To Prevent Alpha-Synuclein Fibrillization in Parkinson’s Disease

  • 期刊论文

  • 发表日期：

    2025年5月17日

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  • Amirhosein Jabbari,
  • Azadeh Niknejad,
  • Najaf Allahyarifard,
  • Leila Karami,
  • Maryam Motamedi

摘要

Purpose

Parkinson’s disease (PD), the second most frequently occurring neurodegenerative disorder. Alpha-synuclein, the principal protein found in Lewy bodies, plays a central role in the disease process of PD. Emerging biochemical and genetic data suggest that the formation of alpha-synuclein inclusion bodies is an early event in disease pathogenesis and is also common to demential with Lewy bodies and multiple system atrophy. This study sought to identify and characterize peptide inhibitors of alpha-synuclein fibrillation as a potential therapeutic strategy.

Methods

The structural and sequence basis for inhibiting alpha-synuclein fibrillation was analyzed from the PDB database concentrating on the residues 60–70 of the NAC region. A six-amino-acid peptide library was designed containing point mutations within that hydrophilic domain, and the most hydrophilic variants were screened by ToxinPred, AlgPred, CPP, BBB, and Haddock servers. Molecular dynamics simulations (100 ns) were performed using GROMACS to assess peptide stability and binding energy. The most suggestive peptide was synthesized using solid-phase synthesis (SPPS), purified using HPLC, and characterized using LC–MS. Fibril inhibition was assessed using thioflavin T (ThT) fluorescence assays, and cell viability was determined with MTT assays using SH-SY5Y cells.

Results

The peptide KEQPTN made the best inhibit alpha-synuclein fibrillation due to its proline residue, enhancing hydrophilicity and thereby preventing aggregation. The in vitro assays confirmed modest fibril reduction with low cytotoxicity, suggesting therapeutic potential.

Conclusion

The peptide brings with it the breath of hope against alpha-synuclein aggregation, a plausible strategy to curb PD. Further studies would be warranted.