Back to Search
Start Over
Design of amyloidogenic peptide traps.
- Source :
-
Nature chemical biology [Nat Chem Biol] 2024 Aug; Vol. 20 (8), pp. 981-990. Date of Electronic Publication: 2024 Mar 19. - Publication Year :
- 2024
-
Abstract
- Segments of proteins with high β-strand propensity can self-associate to form amyloid fibrils implicated in many diseases. We describe a general approach to bind such segments in β-strand and β-hairpin conformations using de novo designed scaffolds that contain deep peptide-binding clefts. The designs bind their cognate peptides in vitro with nanomolar affinities. The crystal structure of a designed protein-peptide complex is close to the design model, and NMR characterization reveals how the peptide-binding cleft is protected in the apo state. We use the approach to design binders to the amyloid-forming proteins transthyretin, tau, serum amyloid A1 and amyloid β <subscript>1-42</subscript> (Aβ42). The Aβ binders block the assembly of Aβ fibrils as effectively as the most potent of the clinically tested antibodies to date and protect cells from toxic Aβ42 species.<br /> (© 2024. The Author(s).)
- Subjects :
- Humans
Protein Binding
Peptides chemistry
Peptides pharmacology
Amyloid chemistry
Amyloid metabolism
Models, Molecular
Peptide Fragments chemistry
Peptide Fragments metabolism
Drug Design
Amyloidogenic Proteins chemistry
Amyloidogenic Proteins metabolism
tau Proteins metabolism
tau Proteins chemistry
Prealbumin chemistry
Prealbumin metabolism
Amino Acid Sequence
Amyloid beta-Peptides chemistry
Amyloid beta-Peptides metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1552-4469
- Volume :
- 20
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Nature chemical biology
- Publication Type :
- Academic Journal
- Accession number :
- 38503834
- Full Text :
- https://doi.org/10.1038/s41589-024-01578-5