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

Design of amyloidogenic peptide traps

Journal Article · Tue Mar 19 04:00:00 EDT 2024 · Nature Chemical Biology

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

^[1]; ^[2]; ^[1]; Rennella, Enrico ^[3]; ^[2]; ^[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.

View Accepted Manuscript (DOE)

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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