A Peptide Strategy for Inhibiting Different Protein Aggregation Pathways.

Autor: Garfagnini T; Institute of Chemistry, The Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram, 9190401, Jerusalem, Israel., Ferrari L; Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, Padualaan 8, 3584, Utrecht CH, The Netherlands.; Science for Life, Utrecht University, Padualaan 8, 3584, Utrecht CH, The Netherlands.; Max Perutz Labs, Vienna BioCenter (VBC), University of Vienna, Vienna, Austria., Koopman MB; Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, Padualaan 8, 3584, Utrecht CH, The Netherlands.; Science for Life, Utrecht University, Padualaan 8, 3584, Utrecht CH, The Netherlands., Dekker FA; Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, Padualaan 8, 3584, Utrecht CH, The Netherlands.; Science for Life, Utrecht University, Padualaan 8, 3584, Utrecht CH, The Netherlands., Halters S; Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, Padualaan 8, 3584, Utrecht CH, The Netherlands.; Science for Life, Utrecht University, Padualaan 8, 3584, Utrecht CH, The Netherlands., Van Kappel E; Oncode Institute, Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, 3584, Utrecht CH, The Netherlands., Mayer G; Institute of Chemistry, The Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram, 9190401, Jerusalem, Israel., Bressler S; Institute of Chemistry, The Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram, 9190401, Jerusalem, Israel., Maurice MM; Oncode Institute, Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, 3584, Utrecht CH, The Netherlands., Rüdiger SGD; Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, Padualaan 8, 3584, Utrecht CH, The Netherlands.; Science for Life, Utrecht University, Padualaan 8, 3584, Utrecht CH, The Netherlands., Friedler A; Institute of Chemistry, The Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram, 9190401, Jerusalem, Israel.
Jazyk: angličtina
Zdroj: Chemistry (Weinheim an der Bergstrasse, Germany) [Chemistry] 2024 Sep 16; Vol. 30 (52), pp. e202400080. Date of Electronic Publication: 2024 Sep 03.
DOI: 10.1002/chem.202400080
Abstrakt: 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.
(© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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