De novo designed protein inhibitors of amyloid aggregation and seeding

Murray, Kevin A.; Hu, Carolyn J.; Griner, Sarah L.; Pan, Hope; Bowler, Jeannette T.; Abskharon, Romany; Rosenberg, Gregory M.; Cheng, Xinyi; Seidler, Paul M.; Eisenberg, David S.

doi:10.1073/pnas.2206240119

De novo designed protein inhibitors of amyloid aggregation and seeding

Journal Article · Mon Aug 15 00:00:00 EDT 2022 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.2206240119· OSTI ID:2470363

^[1]; Hu, Carolyn J. ^[1]; Griner, Sarah L. ^[1]; Pan, Hope ^[1]; Bowler, Jeannette T. ^[1]; Abskharon, Romany ^[1]; Rosenberg, Gregory M. ^[1]; Cheng, Xinyi ^[1]; Seidler, Paul M. ^[2]; ^[1]

University of California, Los Angeles, CA (United States)
University of Southern California, Los Angeles, CA (United States)

Neurodegenerative diseases are characterized by the pathologic accumulation of aggregated proteins. Known as amyloid, these fibrillar aggregates include proteins such as tau and amyloid-β (Aβ) in Alzheimer’s disease (AD) and alpha-synuclein (αSyn) in Parkinson’s disease (PD). The development and spread of amyloid fibrils within the brain correlates with disease onset and progression, and inhibiting amyloid formation is a possible route toward therapeutic development. Recent advances have enabled the determination of amyloid fibril structures to atomic-level resolution, improving the possibility of structure-based inhibitor design. In this work, we use these amyloid structures to design inhibitors that bind to the ends of fibrils, “capping” them so as to prevent further growth. Using de novo protein design, we develop a library of miniprotein inhibitors of 35 to 48 residues that target the amyloid structures of tau, Aβ, and αSyn. Biophysical characterization of top in silico designed inhibitors shows they form stable folds, have no sequence similarity to naturally occurring proteins, and specifically prevent the aggregation of their targeted amyloid-prone proteins in vitro. The inhibitors also prevent the seeded aggregation and toxicity of fibrils in cells. In vivo evaluation reveals their ability to reduce aggregation and rescue motor deficits in Caenorhabditis elegans models of PD and AD.

View Accepted Manuscript (DOE)

Research Organization:: University of California, Los Angeles, CA (United States)

Sponsoring Organization:: USDOE; US Public Health Service National Research Service; National Institutes of Health (NIH)

OSTI ID:: 2470363

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 34 Vol. 119; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
Alpha-synuclein
Amyloid
Amyloid-beta
Biological Sciences
Biophysics and Computational Biology
Protein design
Science & Technology
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De novo designed protein inhibitors of amyloid aggregation and seeding

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References (58)

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