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Updated: Jul 5, 2025
Generation of Alpha-Synuclein Preformed Fibrils from Monomers and Use In Vivo
Published on: June 2, 2019
Characterizing fibril morphological changes by spirooxindoles for neurodegenerative disease application
Anthony Dahdah1, Nilamuni H de Silva1, Subashani Maniam1
1School of Science, STEM College, RMIT University, 124 La Trobe Street, Melbourne, VIC, 3001, Australia. Ewan.blanch@rmit.edu.au.
Abstract:
Fibrillation of proteins and polypeptides, which leads to the deposition of plaques in cells and tissues has been widely associated with many neuropathological diseases. Inhibition of protein misfolding and aggregation is crucial for the prevention and treatment of these conditions. The growing interest in identifying inhibitor molecules to prevent the formation of fibrils in vivo has led to the results highlighted in this study. Due to their hydrophobic structure and potential to readily cross the blood brain barrier, a library of spirooxindole compounds were synthesized with those labelled Hd-63, Hd-66 and Hd-74 proving to be the most potent against fibril formation. Our spectroscopic analysis provides detailed insight, that the introduction of these spirooxindole compounds leads to morphological changes in the mechanism of fibril formation which prevent the formation of highly ordered fibrils, instead results in the formation of disordered aggregates which are not fibrillar in nature.
Insights
New spirooxindole compounds show promise in preventing protein fibrillation, a key factor in neuropathological diseases. These molecules disrupt the formation of harmful fibrils, leading to disordered aggregates instead.
Area of Science:
- Neuroscience
- Biochemistry
- Medicinal Chemistry
Background:
- Protein fibrillation and plaque deposition are linked to neuropathological diseases.
- Inhibiting protein misfolding and aggregation is vital for disease prevention and treatment.
- Identifying effective inhibitor molecules for in vivo use is an active research area.
Purpose of the Study:
- To synthesize and evaluate spirooxindole compounds as inhibitors of protein fibril formation.
- To investigate the mechanism by which these compounds affect fibril assembly.
Main Methods:
- Synthesis of a library of spirooxindole compounds.
- Spectroscopic analysis to study the effects of compounds on protein aggregation.
- Morphological characterization of fibril formation in the presence of inhibitors.
Main Results:
- Spirooxindole compounds, particularly Hd-63, Hd-66, and Hd-74, demonstrated potent inhibition of fibril formation.
- These compounds possess hydrophobic structures and the potential to cross the blood-brain barrier.
- Spectroscopic data revealed that the compounds alter fibril formation, resulting in disordered aggregates rather than highly ordered fibrils.
Conclusions:
- Spirooxindole derivatives are effective inhibitors of protein fibrillation.
- The identified compounds offer a promising therapeutic strategy for neuropathological conditions.
- Further research into these compounds could lead to novel treatments for diseases associated with protein aggregation.
