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PreprintCited by 48Alzheimer's disease research and treatmentsProtein Structure and DynamicsChemical Synthesis and Analysis

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Design of amyloidogenic peptide traps

Open access
Sahtoe, Danny D., Andrzejewska, Ewa A., Han, Hannah L., Rennella, Enrico, Schneider, Matthias M., Meisl, Georg, Ahlrichs, Maggie, Decarreau, Justin, Nguyen, Hannah, Kang, Alex, Levine, Paul, Lamb, Mila, Li, Xinting, Bera, Asim K., Kay, Lewis E., Knowles, Tuomas P.J., Baker, David·2023·Nature Chemical Biology
DOI 10.1101/2023.01.13.523785PMC PMC11288891

Preprint — published as 10.1038/s41589-024-01578-5 · Paper page

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Abstract

Segments of proteins with β-strand propensity can self associate to form amyloid fibrils associated with many diseases. These regions often adopt alternative structures in their folded states, or are intrinsically disordered in solution, making it difficult to generate binders or inhibitors with existing strategies. Here 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 flanked by β-strands that form hydrogen bonds to the peptide upon binding. The designs bind their cognate peptides in vitro with nanomolar affinities and in mammalian cells. 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 segments of the amyloid forming proteins Transthyretin, Tau, Serum amyloid A1 and Aβ42. The Aβ binders block assembly of Aβ fibrils as effectively as the most potent of the clinically tested antibodies to date.

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Metadata

Authors
Sahtoe, D. D., Andrzejewska, E. A., Han, H. L., Rennella, E., Schneider, M. M., Meisl, G., Ahlrichs, M., Decarreau, J., Nguyen, H., Kang, A., Levine, P., Lamb, M., Li, X., Bera, A. K., Kay, L. E., Knowles, T. P. J., & Baker, D.
Affiliations
  • Howard Hughes Medical Institute (US)
  • University of Cambridge (GB)
  • University of Washington (US)
  • University of Toronto (CA)
Corresponding author
  • Sahtoe, Danny D.
  • Baker, David
ORCID
Venue
Nature Chemical Biology
Publisher
openRxiv
Published
2023-01-13
Volume
20
Issue
8
Pages
981-990
ISSN
1552-4450 (ISSN-L)
DOI
10.1101/2023.01.13.523785
PMC
PMC11288891
OpenAlex
W4392956053
Cited by
48
References
1
Citations by year
2026: 16 · 2025: 21 · 2024: 6 · 2023: 5
FWCI
12.14
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Nature Chemical Biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (publishedVersion, other-oa)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
Funders
  • U.S. Department of Energy (DE‐ AC02‐06CH11357, Contract No. DE-AC02-06CH11357., AC02‐06CH11357, P30 GM124165, 06CH11357, No. DE-AC02-06CH11357, DE-AC02-)
  • Amgen
  • National Institutes of Health (DE-AC02–06CH11357, GM124165)
  • Defense Advanced Research Projects Agency (HR0011-21-2-0012, HR001120S0052)
  • Office of Science (Contract No. DE-AC02-06CH11357, AC02‐06CH11357, DE-AC02, No. DE-AC02-06CH11357., 06CH11357, DE-AC02-06CH11357)
  • Canadian Institutes of Health Research (503573, FND-503573)
  • Natural Sciences and Engineering Research Council of Canada (DE-AC02-06CH11357, 2015-04347)
  • National Institute of General Medical Sciences (DE-AC02-06CH11357, GM124165, P30GM124165)
  • Argonne National Laboratory (DE- AC02-06-CH11357, DE-AC02, AC02–06CH11357, No. DE-AC02-06CH11357, 06CH11357, Contract No. DE-AC02-06CH11357., P30 GM124165)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
Keywords
amyloid fibril formation, amyloidogenic peptides, de novo protein design, beta-hairpin, protein-peptide complex, prealbumin, tau protein, serum amyloid A1, amyloid-beta 42, amyloidosis
MeSH terms
Amino Acid Sequence, Amyloid, Humans, Models, Molecular, Peptide Fragments, Peptides, Prealbumin, Protein Binding, Drug Design, Amyloid beta-Peptides, tau Proteins, Amyloidogenic Proteins

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