Backbone Thioamide Substitution Enhances the Activity of Short Peptides in Modulating the Aggregation of α-Synuclein
Year: 2026
Type: preprint
Abstract: The non-amyloid-β component (NAC) region of the Parkinson’s-associated protein α-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, 66 VGGAVVT 72 , can be reprogrammed through backbone engineering to modulate α-synuclein aggregation. Backbone thioamide substitution of this peptide enhances its interactions with α-synuclein fibrils and accelerates aggregation, whereas N -methylation disrupts β-sheet hydrogen bonding and inhibits fibrillization. Strikingly, combining these modifications yields hybrid peptides that inhibit the fibrillization of full-length α-synuclein at sub-stoichiometric concentrations. Consistent with in vitro results, these backbone-modified peptides can also reduce seeded α-synuclein aggregation in cells. These results establish that minimal amyloidogenic sequences can be systematically tuned from aggregation promoters to inhibitors through backbone-level perturbations, particularly thioamide incorporation.
Institutions: The University of Texas at Austin, University of Michigan
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7204264417
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