A Peptide Strategy for Inhibiting Different Protein Aggregation Pathways
Abstract: Protein aggregation correlates with many human diseases. Protein aggregates differ in structure and shape. Strategies to develop effective aggregation inhibitors that reach the clinic failed so far. Here, we developed a family of peptides targeting early aggregation stages for both amorphous and fibrillar aggregates of proteins unrelated in sequence and structure. They act on dynamic precursors before mechanistic differentiation takes place. Using peptide arrays, we first identified peptides inhibiting the amorphous aggregation of a molten globular, aggregation‐prone mutant of the Axin tumor suppressor. Optimization revealed that the peptides activity did not depend on their sequences but rather on their molecular determinants: a composition of 20–30 % flexible, 30–40 % aliphatic and 20–30 % aromatic residues, a hydrophobicity/hydrophilicity ratio close to 1, and an even distribution of residues of different nature throughout the sequence. The peptides also suppressed fibrillation of Tau, a disordered protein that forms amyloids in Alzheimer's disease, and slowed down that of Huntingtin Exon1, an amyloidogenic protein in Huntington's disease, both entirely unrelated to Axin. Our compounds thus target early stages of different aggregation mechanisms, inhibiting both amorphous and amyloid aggregation. Such cross‐mechanistic, multi‐targeting aggregation inhibitors may be lead compounds for developing drug candidates against various protein aggregation diseases.
- Location
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Deutsche Nationalbibliothek Frankfurt am Main
- Extent
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Online-Ressource
- Language
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Englisch
- Bibliographic citation
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A Peptide Strategy for Inhibiting Different Protein Aggregation Pathways ; volume:30 ; number:52 ; year:2024 ; extent:11
Chemistry - a European journal ; 30, Heft 52 (2024) (gesamt 11)
- Creator
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Garfagnini, Tommaso
Ferrari, Luca
Koopman, Margreet B.
Dekker, Françoise A.
Halters, Sem
Van Kappel, Eline
Mayer, Guy
Bressler, Shachar
Maurice, Madelon M.
Rüdiger, Stefan G. D.
Friedler, Assaf
- DOI
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10.1002/chem.202400080
- URN
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urn:nbn:de:101:1-2410011421022.530867329916
- Rights
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Last update
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15.08.2025, 7:27 AM CEST
Data provider
Deutsche Nationalbibliothek. If you have any questions about the object, please contact the data provider.
Associated
- Garfagnini, Tommaso
- Ferrari, Luca
- Koopman, Margreet B.
- Dekker, Françoise A.
- Halters, Sem
- Van Kappel, Eline
- Mayer, Guy
- Bressler, Shachar
- Maurice, Madelon M.
- Rüdiger, Stefan G. D.
- Friedler, Assaf
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Monitoring Alzheimer Amyloid Peptide Aggregation by EPR
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Oxidation destabilizes toxic amyloid beta peptide aggregation
Extracellular phosphorylation of the Amyloid β-peptide [beta-peptide] promotes aggregation
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Beta-Peptide Helices As Transmembrane Domains: Aggregation, Recognition and Lipid-Peptide Interaction
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Inhibition of peptide aggregation by means of enzymatic phosphorylation
Impact of multivalent charge presentation on peptide–nanoparticle aggregation
Synthetic RGDS peptide attenuates lipopolysaccharide-induced pulmonary inflammation by inhibiting integrin signaled MAP kinase pathways
Peptide Aggregation Induced Immunogenic Rupture (PAIIR)
Etidronate prevents dystrophic cardiac calcification by inhibiting macrophage aggregation
Monitoring Alzheimer Amyloid Peptide Aggregation by EPR
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Oxidation destabilizes toxic amyloid beta peptide aggregation
Extracellular phosphorylation of the Amyloid β-peptide [beta-peptide] promotes aggregation
Tau Aggregation Inhibiting Peptides as Potential Therapeutics for Alzheimer Disease
Beta-Peptide Helices As Transmembrane Domains: Aggregation, Recognition and Lipid-Peptide Interaction
Molecular mechanisms and peptide-based modulators of protein aggregation
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