Backbone Thioamide Substitution Enhances the Activity of Short Peptides in Modulating the Aggregation of α-Synuclein
The non-amyloid-{beta} component (NAC) region of the Parkinson's-associated protein -synuclein plays a key role in its pathogenic aggregation, motivating the development of molecules that target this critical region. Here, we show that a minimal NAC-derived motif, 66VGGAVVT72, can be reprogrammed through backbone engineering to modulate -synuclein aggregation. Backbone thioamide substitution of…
Recent research has revealed that manipulating the backbone structure of a short peptide derived from the Parkinson's-associated protein α-synuclein can alter its ability to modulate the protein's aggregation. The non-amyloid-beta component (NAC) region of α-synuclein is crucial in its pathogenic aggregation, making it an attractive target for therapeutic intervention.
By altering the backbone of a minimal peptide, 66VGGAVVT72, researchers were able to enhance its interactions with α-synuclein fibrils and accelerate aggregation. Conversely, N-methylation disrupts beta-sheet hydrogen bonding and inhibits fibrillization. When these modifications are combined, they create hybrid peptides that can inhibit the fibrillization of full-length α-synuclein even at very low concentrations.
These findings, supported by in vitro experiments, suggest that minimal amyloidogenic sequences can be fine-tuned through backbone-level modifications, transforming aggregation promoters into inhibitors.
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