ROSETTA-informed design of structurally stabilized cyclic anti-amyloid peptides

Area of Science:

• Neuroscience
• Biochemistry
• Computational Chemistry

Background:

• Beta-amyloid (Aβ) oligomers are key toxic species in Alzheimer's disease pathogenesis.
• Transthyretin binds Aβ oligomers via its inner β-sheet (strands G/H), acting as a natural inhibitor.
• A linear peptide mimicking this binding site showed moderate Aβ inhibition.

Purpose of the Study:

• To enhance the efficacy and stability of a β-amyloid binding peptide.
• To investigate structural modifications for improved inhibition of β-amyloid aggregation.
• To identify optimal design features for potent amyloid inhibitors.

Main Methods:

• Designed and synthesized linear and cyclic peptides based on transthyretin's Aβ binding domain.
• Employed ROSETTA computational modeling to predict cyclic peptide conformations and stability.
• Assessed synthesized peptides for secondary structure, proteolytic stability, and inhibition of Aβ aggregation.

Main Results:

• Cyclization and incorporation of β-turn templates significantly improved peptide stability and Aβ inhibitory efficacy.
• Computational and experimental data indicated that conformational homogeneity and β-sheet structure are beneficial.
• Disulfide bond formation across β-strands was found to be detrimental to inhibitory function.

Conclusions:

• Optimized cyclic peptides incorporating β-sheet structure and conformational homogeneity represent a promising strategy for inhibiting β-amyloid aggregation.
• Design principles derived from this study can guide the development of more effective Alzheimer's disease therapeutics.
• Structural disorder and non-specific disulfide linkages should be avoided in designing peptide-based amyloid inhibitors.