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Amyloids and antimicrobial peptides have traditionally been recognized as distinct families with separate biological functions and targets. However, certain amyloids and antimicrobial peptides share structural and functional characteristics that contribute to the development of neurodegenerative diseases. Specifically, the aggregation of amyloid-β (Aβ) and microbial infections are interconnected pathological factors in Alzheimer’s disease (AD). In this study, we propose and demonstrate a novel repurposing strategy for an antimicrobial peptide of protegrin-1 (PG-1), which exhibits the ability to simultaneously prevent Aβ aggregation and microbial infection both in vitro and in vivo. Through a comprehensive analysis using protein, cell, and worm assays, we uncover multiple functions of PG-1 against Aβ, including the following: (i) complete inhibition of Aβ aggregation at a low molar ratio of PG-1/Aβ = 0.25:1, (ii) disassembly of the preformed Aβ fibrils into amorphous aggregates, (iii) reduction of Aβ-induced cytotoxicity in SH-SY5Y cells and transgenic GMC101 nematodes, and (iv) preservation of original antimicrobial activity against P.A., E.coli., S.A., and S.E. strains in the presence of Aβ. Mechanistically, the dual anti-amyloid and anti-bacterial functions of PG-1 primarily arise from its strong binding to distinct Aβ seeds (KD = 1.24–1.90 μM) through conformationally similar β-sheet associations. This work introduces a promising strategy to repurpose antimicrobial peptides as amyloid inhibitors, effectively targeting multiple pathological pathways in AD.
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N -Amino peptide scanning reveals inhibitors of Aβ 42 aggregation
The aggregation of amyloids into toxic oligomers is believed to be a key pathogenic event in the onset of Alzheimer's disease. Peptidomimetic modulators capable of destabilizing the propagation of an extended network of β-sheet fibrils represent a potential intervention strategy. Modifications to amyloid-beta (Aβ) peptides derived from the core domain have afforded inhibitors capable of both antagonizing aggregation and reducing amyloid toxicity. Previous work from our laboratory has shown that peptide backbone amination stabilizes β-sheet-like conformations and precludes β-strand aggregation. Here, we report the synthesis of N -aminated hexapeptides capable of inhibiting the fibrillization of full-length Aβ 42 . A key feature of our design is N -amino substituents at alternating backbone amides within the aggregation-prone Aβ 16–21 sequence. This strategy allows for maintenance of an intact hydrogen-bonding backbone edge as well as side chain moieties important for favorable hydrophobic interactions. An N -amino scan of Aβ 16–21 resulted in the identification of peptidomimetics that block Aβ 42 fibrilization in several biophysical assays.
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- PAR ID:
- 10175267
- Date Published:
- Journal Name:
- RSC Advances
- Volume:
- 10
- Issue:
- 24
- ISSN:
- 2046-2069
- Page Range / eLocation ID:
- 14331 to 14336
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/D0RA02009E
