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Known as amyloid, these fibrillar aggregates include proteins such as tau and amyloid-\u03b2 (A\u03b2) in Alzheimer\u2019s disease (AD) and alpha-synuclein (\u03b1Syn) in Parkinson\u2019s 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, \u201ccapping\u201d 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, A\u03b2, and \u03b1Syn. 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\u00a0vitro. 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\n                    <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                    models of PD and AD.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2206240119","type":"journal-article","created":{"date-parts":[[2022,8,15]],"date-time":"2022-08-15T15:21:26Z","timestamp":1660576886000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":85,"title":["De novo designed protein inhibitors of amyloid aggregation and seeding"],"prefix":"10.1073","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1969-7701","authenticated-orcid":false,"given":"Kevin A.","family":"Murray","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095-1569"},{"name":"Department of Biological Chemistry, University of California, Los Angeles\u2013Department of 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