Design of amyloidogenic peptide traps

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 J.; Baker, David

doi:10.1038/s41589-024-01578-5

Title: Design of amyloidogenic peptide traps

Journal Article · 19 March 2024 · Nature Chemical Biology

DOI: https://doi.org/10.1038/s41589-024-01578-5 · OSTI ID:2470233

^[1];

^[2];

^[1]; Rennella, Enrico ^[3];

^[2];

^[1]; Decarreau, Justin ^[1];

^[1]; Kang, Alex ^[1]; Levine, Paul ^[1]; Lamb, Mila ^[1]; Li, Xinting ^[1];

^[1]; Kay, Lewis E. ^[4];

^[2];

^[1]

Univ. of Washington, Seattle, WA (United States)
Univ. of Cambridge (United Kingdom)
Univ. of Toronto, ON (Canada)
Univ. of Toronto, ON (Canada); The Hospital for Sick Children Research Inst., Toronto, ON (Canada)

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_1–42 (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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 2470233

Journal Information:: Nature Chemical Biology, Journal Name: Nature Chemical Biology Journal Issue: 8 Vol. 20; ISSN 1552-4450

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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