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.
- Standort
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Deutsche Nationalbibliothek Frankfurt am Main
- Umfang
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Online-Ressource
- Sprache
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Englisch
- Erschienen in
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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)
- Urheber
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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
- Rechteinformation
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Letzte Aktualisierung
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15.08.2025, 07:27 MESZ
Datenpartner
Deutsche Nationalbibliothek. Bei Fragen zum Objekt wenden Sie sich bitte an den Datenpartner.
Beteiligte
- 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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