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Updated: Mar 19, 2026
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Paramagnetic Relaxation Enhancement for Detecting and Characterizing Self-Associations of Intrinsically Disordered Proteins
Published on: September 23, 2021
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A Chirality-Guided Molecular Recognition Strategy for Targeting Intrinsically Disordered Proteins.
Kenta Morita1,2, Shiho Seguchi1, Ayaka Hayashi1
1Department of Chemical Science and Engineering, Graduate School of Engineering, Kobe University, Kobe, Japan.
Chemistry (Weinheim an Der Bergstrasse, Germany)
|March 18, 2026
Summary
Peptide stereocomplexation, driven by hydrophobic and electrostatic forces, enables targeted inhibition of amyloid beta 42 (Aβ42) aggregation. This strategy offers a novel approach for developing therapeutics against intrinsically disordered proteins.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Peptide stereocomplexation is known but sequence-dependent conditions are unclear.
- Amyloid beta 42 (Aβ42) is a pathological intrinsically disordered protein implicated in neurodegenerative diseases.
Purpose of the Study:
- To systematically investigate peptide stereocomplexation using short tripeptides.
- To elucidate sequence-dependent conditions for stereocomplexation.
- To design a D-peptide targeting Aβ42 based on stereocomplexation insights.
Main Methods:
- Aggregate formation in mixed aqueous solutions.
- Single-crystal X-ray diffraction.
- Calorimetry, simulations, and fluorescence assays.
Main Results:
- Stereocomplexation was driven by hydrophobic and electrostatic interactions.
- Racemic crystals were observed via X-ray diffraction.
- A rationally designed D-peptide inhibited Aβ42 fibrillization and cytotoxicity in cells, outperforming RD2.
Conclusions:
- Peptide stereocomplexation is a viable strategy for designing sequence-targeting ligands.
- This approach is effective against intrinsically disordered proteins like Aβ42.
- Developed D-peptide shows therapeutic potential against Aβ42-related pathologies.
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